WO2000055141A1 - Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them - Google Patents

Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them Download PDF

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Publication number
WO2000055141A1
WO2000055141A1 PCT/EP2000/002228 EP0002228W WO0055141A1 WO 2000055141 A1 WO2000055141 A1 WO 2000055141A1 EP 0002228 W EP0002228 W EP 0002228W WO 0055141 A1 WO0055141 A1 WO 0055141A1
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Prior art keywords
group
alkyl
substituted
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hereinbefore defined
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PCT/EP2000/002228
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French (fr)
Inventor
Frank Himmelsbach
Elke Langkopf
Stefan Blech
Birgit Jung
Thomas Metz
Flavio Solca
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Priority to HK02104697.6A priority Critical patent/HK1043124B/en
Priority to AU31667/00A priority patent/AU772520B2/en
Priority to NZ514706A priority patent/NZ514706A/en
Priority to EEP200100484A priority patent/EE05034B1/en
Priority to HU0201832A priority patent/HUP0201832A3/en
Priority to JP2000605571A priority patent/JP3754617B2/en
Priority to AT00909360T priority patent/ATE305456T1/en
Priority to SI200030768T priority patent/SI1163227T1/en
Priority to EP00909360A priority patent/EP1163227B1/en
Priority to MEP-456/08A priority patent/MEP45608A/en
Priority to UA2001107007A priority patent/UA71610C2/en
Priority to EA200100922A priority patent/EA005098B1/en
Priority to BR0009076-0A priority patent/BR0009076A/en
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to DE60022866T priority patent/DE60022866T2/en
Priority to PL350522A priority patent/PL205726B1/en
Priority to CA002368059A priority patent/CA2368059C/en
Priority to SK1303-2001A priority patent/SK286959B6/en
Publication of WO2000055141A1 publication Critical patent/WO2000055141A1/en
Priority to IL144626A priority patent/IL144626A/en
Priority to US09/938,235 priority patent/US20020177601A1/en
Priority to NO20014487A priority patent/NO327747B1/en
Anticipated expiration legal-status Critical
Priority to US11/266,920 priority patent/US20060063752A1/en
Priority to US12/423,522 priority patent/US20090203683A1/en
Ceased legal-status Critical Current

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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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Definitions

  • the present invention relates to bicyclic heterocyclic compounds of general formula
  • R a denotes a hydrogen atom or a C 1 . 4 -alkyl group
  • R b denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst
  • R- L and R 2 which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
  • R 3 denotes a hydrogen, fluorine, chlorine or bromine atom
  • R c and R d which may be identical or different, each denote a hydrogen, fluorine or chlorine atom, a methoxy group or a methyl group optionally substituted by a methoxy, dimethyl- amino, diethylamino, pyrrolidino, piperidino or morpholino group,
  • X denotes a methine group substituted by a cyano group or a nitrogen atom
  • A denotes an -0-C 1 . 6 -alkylene, -0-C 4 . 7 -cycloalkylene, -O-C JL . 3 -alkylene-C 3 . 7 -cycloalkylene, -0-C 4 _ 7 -cyclo- alkylene-C 1-3 -alkylene or -0-C 1 . 3 -alkylene-C 3 . 7 -cycloal- kylene-C ⁇ -alkylene group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
  • an -0-C 2 . 6 -alkylene group which is substituted from position 2 onwards by a hydroxy, C- ⁇ -alkoxy, amino, C 1-4 -alkylamino, di- (C 1 . 4 -alkyl) -amino, pyrrolidino, piperidino, morpholino, pipera- zino or 4- (C 1-4 -alkyl) -piperazino group and the oxygen atom of the abovementioned-0-C 2 .
  • s -alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
  • R 4 denotes a hydrogen atom or a C 1 . 4 -alkyl group
  • R 6 0-CO-alkylene-NR s (R 7 0-PO-OR 8 ) -alkylene-NR 5 or (R 7 0-PO-R 9 ) -alkylene-NR s group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C 1.2 -alkyl groups or by an R 6 0-C0 or group, whilst
  • R 5 denotes a hydrogen atom
  • a C 2 . 4 -alkyl group which is substituted from position 2 by a hydroxy, C 1 . 4 -alkoxy, amino, C 1 . 4 -alkylamino or di- (C 1 . 4 -al- kyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C 1 . 4 -alkyl) -imino group,
  • R 6 , R 7 and R 8 which may be identical or different, in each case denote a hydrogen atom
  • Ci .g -alkyl group which may be substituted from position 2 onwards by a hydroxy, C ⁇ -alkoxy, amino, C ⁇ -alkylamino or di- (C ⁇ -alkyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C ⁇ -alkyl) - imino group,
  • R e and R f which may be identical or different, in each case denote a hydrogen atom or a C 1 . 4 -alkyl group and
  • R g denotes a C 1 . 4 -alkyl, C 3-7 -cycloalkyl, C 1-4 -alkoxy or C 5-7 -cycloalkoxy group,
  • R 9 denotes a C ⁇ -alkyl, aryl or aryl-C ⁇ ,,-alky1 group
  • R 6 0-CO a 4- to 7-membered alkyleneimino group which is substituted by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , bis- (R 6 0-CO) -C 1 . 4 -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) - C ⁇ -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R 6 0-CO a piperazino or homopiperazino group which is substituted in the 4 position by the group R 10 and additionally at a cyclic carbon atom by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R 6 0-CO- C 1-4 -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl , (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group wherein R 6 to R 9 are as hereinbefore defined and
  • R 10 denotes a hydrogen atom, a C 1 . 4 -alkyl, formyl, C 1 . 4 -alkylcarbonyl or C 1 . 4 -alkylsulphonyl group,
  • a piperazino or homopiperazino group which is substituted in the 4 position by the group R 10 and is additionally substituted at cyclic carbon atoms by two R 6 0-CO or R 6 0-CO-C x .
  • 4 -alkyl groups or by an R 6 0-CO group and an group wherein R 6 and R 10 are as hereinbefore defined a piperazino or homopiperazino group which is substituted in each case in the 4 position by an bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) - C ⁇ -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R 6 0-CO a orpholino or homomorpholino group which is substituted in each case by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , kyl, bis- (R 6 0-CO) -C 1-4 -alkyl, (R 7 0-PO-OR 8 ) -C 1-4 -alkyl or (R 7 0-PO-R 9 ) -C 1 . 4 -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R 6 0-CO a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R 10 , whilst the above- mentioned 5 to 7-membered rings are in each case additionally substituted at a carbon atom by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R g O-CO-C ⁇ -alkyl, bis- (R 6 0-CO) -C 1 . 4 -alkyl, (R 7 0-PO-OR 8 ) -C 1 . 4 -alkyl or (R 7 0-PO-R 9 ) -C x . 4 -alkyl group wherein R 6 to R 10 are as hereinbefore defined,
  • R 6 and R 10 are as hereinbefore defined, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an bis- (RgO-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) - C 1 . 4 -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C x . 4 -alkyl group, whilst R 6 to R 9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups in each case are linked to a carbon atom of the group A,
  • R X1 denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahy- drofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahy- dropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two methyl groups,
  • a and B together denotes a hydrogen, fluorine or chlorine atom
  • Ci.g-alkoxy group a C 2 . 6 -alkoxy group which is substituted from position 2 onwards by a hydroxy, C 1-4 -alkoxy, amino, C 1 . 4 -alkylamino, di- (C ⁇ -al- kyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C 1 . 4 -alkyl) -piperazino, homopiperazino, 4- (C ⁇ -alkyl) -homopiperazino or 1-imidazolyl group,
  • R 6 0-CO R 7 0-PO-OR 8
  • R 7 0-PO-R 9 R 6 to R 9
  • C denotes an -0-C 1-6 -alkylene, -0-C 4 . 7 -cycloalkylene, -D-C ⁇ -al- kylene-C 3 . 7 -cycloalkylene, -0-C 4-7 -cycloalkylene-C 1-3 -alkylene or -0-C 1.3 -alkylene-C 3 . 7 -cycloalkylene-C 1-3 -alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
  • NR 4 group where the latter is linked to a carbon atom of the group D and R 4 is as hereinbefore defined
  • D denotes an R 6 0-CO-alkylene-NR 5 , (R 7 0-PO-OR 8 ) -alkylene-NR 5 or (R 7 0-PO-R 9 ) -alkylene-NR 5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C ⁇ -alkyl groups or by an R 6 0-CO or group, whilst R 5 to R 9 are as hereinbefore defined,
  • R 6 to R 9 a 4- to 7-membered alkyleneimino group which is substituted by an R g O-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R 6 0-CO-C 1-4 -alkyl , bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C x . 4 -al yl or (R 7 0-PO-R 9 ) - C 1-4 -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R 6 is as hereinbefore defined, a piperazino or homopiperazino group which is substituted in the 4 position by the group R 10 and additionally at a cyclic carbon atom by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R 6 0-CO- C 1-4 -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group wherein R 6 to R 1Q are as hereinbefore defined,
  • R 6 0-C0 a morpholino or homomorpholino group which is substituted in each case by an R 6 0-C0, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R g O-CO- C ⁇ -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C 1-4 -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • a morpholino or homomorpholino group which is substituted by two R g O-CO or R 6 0-CO-C 1-4 -alkyl groups or by an R 6 0-CO group and an R g O-CO-C ⁇ -alkyl group wherein R 6 is as hereinbefore defined, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R 10 , whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R 6 0-C0, (R 7 0-P0-0R 8 ) , (R 7 0-P0-R 9 ) , R 6 0-CO-C 1 .
  • R 6 0-CO-C 1 . 4 -alkyl bis- (R s O-CO) - C 1-4 -alkyl, (R 7 0-PO-OR 8 ) -C 1-4 -alkyl or (R 7 0-PO-R 9 ) -C 1-4 -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a C ⁇ -alkyl, RgO-CO-C 1-4 -alkyl, (R 7 0-PO-OR 8 ) -C 1-4 -alkyl or (R 7 0-PO-R 9 ) -C x . 4 -alkyl group, whilst R 6 to R 9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups are in each case linked to a carbon atom of the group C,
  • R 1X NR 5 group wherein R s and R xl are as hereinbefore defined, or
  • C and D together denote a hydrogen, fluorine or chlorine atom
  • a C 2 . 6 -alkoxy group which is substituted from position 2 by a hydroxy, C ⁇ -alkoxy, amino, C ⁇ -alkylamino, di- (C 1 . 4 -alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C 1 . 4 -alkyl) -piperazino, homopiperazino, 4- (C ⁇ -alkyl) -homopiperazino or 1-imidazolyl group,
  • RgO-CO R 7 0-PO- 0R 8
  • R 7 0-PO-R 9 R 6 to R 9
  • At least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, an (R 7 0-PO-OR 8 ) or (R 7 0-PO- R 9 ) group, or
  • At least one of the groups B or D contains an optionally substituted 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran- 4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group, or
  • At least one of the groups A, B, C or D or A together with B or C together with D contains an R 6 0-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group.
  • aryl moieties mentioned in the definition of the above- mentioned groups is meant a phenyl group which may in each case be monosubstituted by R 12 , mono-, di- or trisubstituted by R 13 or monosubstituted by R 12 and additionally mono- or disub- stituted by R 13 , whilst the substituents may be identical or different and
  • R 12 denotes a cyano, carboxy, C ⁇ -alkoxycarbonyl, aminocarbo- nyl, C ⁇ -alkylaminocarbonyl, di- (C ⁇ -alkyl) -aminocarbonyl, C ⁇ -alkylsulphenyl, C 1-4 -alkylsulphinyl, C ⁇ _ 4 -alky1sulphonyl, hydroxy, C 1 .
  • R a to R d , A and X are as hereinbefore defined,
  • R 6 0-CO-alkylene-NR 5 (R 7 0-PO-OR 8 ) -alkylene-NR 5 or (R 7 0-PO-R 9 ) -alkylene-NR 5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C ⁇ -alkyl groups or by ah R 6 0-CO or R 6 0-CO-C 1 . 2 -alkyl group,
  • R g O-CO an R g O-CO
  • R 7 0-PO-OR 8 a 4- to 7-membered alkyleneimino group which is substituted by an R g O-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R 6 0-CO-C 1 . 4 -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) - C- ⁇ -alkyl group,
  • R 6 0-CO a piperazino or homopiperazino group which is substituted in the 4 position by the group R 10 and additionally at a cyclic carbon atom by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R 6 0-CO- C 1-4 -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C 1-4 -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group,
  • a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a C- ⁇ -alkyl, R 6 0-CO-C 1 _ 4 -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group, whilst R 6 to R 9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups in each case are linked to a carbon atom of the group A, or
  • a and B together denote a hydrogen, fluorine or chlorine atom
  • a C 2 . s -alkoxy group which is substituted from position 2 by a hydroxy, C 1 . 4 -alkoxy, amino, C 1 . 4 -alkylamino, di- (C ⁇ -alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C ⁇ -alkyl) -piperazino, homopiperazino or 4- (C 1-4 -alkyl) -homopiperazino group,
  • C denotes an -0-C 4 . 7 -cycloalkylene, -0-C 1 . 3 -al- kylene-C 3 . 7 -cycloalkylene, -0-C 4 . 7 -cycloalkylene-C 1-3 -alkylene or -0-C 1 . 3 -alkylene-C 3 _ 7 -cycloalkylene-C 1 _ 3 -alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
  • an -0-C 2-6 -alkylene group which is substituted from position 2 onwards by a hydroxy, C ⁇ -alkoxy, amino, C- ⁇ -alkylamino, di- (C.,_ 4 -alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C ⁇ -alkyl) -piperazino group,
  • D denotes an R 6 0-CO-alkylene-NR 5 , (R 7 O-PO-0R 8 ) -alkylene-NR s or (R 7 0-PO-R 9 ) -alkylene-NR 5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C 1 .
  • R 6 0-CO or R 6 0-CO-C 1-2 -alkyl group a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , bis- (R g O-CO) -C 1 . 4 -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) - C ⁇ -alkyl group,
  • R 6 0-CO a piperazino or homopiperazino group which is substituted in the 4 position by the group R 10 and additionally at a cyclic carbon atom by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , R 6 0-CO- C ⁇ -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C 1-4 -alkyl group,
  • a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R 10 whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R 6 0-CO, (R 7 0-PO-OR 8 ) , (R 7 0-PO-R 9 ) , , bis- (R 6 0-CO) - C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group,
  • a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a (R 7 O-P0-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) -C ⁇ -alkyl group, whilst R 6 to R 9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups are in each case linked to a carbon atom of the group C, or
  • C and D together denote a hydrogen, fluorine or chlorine atom
  • a C 2 . 6 -alkoxy group which is substituted from position 2 by a hydroxy, C 1-4 -alkoxy, amino, C 1-4 -alkylamino, di- (C ⁇ -alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C ⁇ -alkyl) -piperazino, homopiperazino or 4- (C ⁇ -alkyl) -homopiperazino group,
  • Ci. g -alkoxy group which is substituted by an R 6 0-CO, (R 7 0-PO- 0R 8 ) or (R 7 0-PO-R 9 ) group,
  • At least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R 7 0-PO-OR 8 ) or (R 7 0-PO- R 9 ) group, or
  • At least one of the groups A, B, C or D or A together with B or C together with D contains an R 6 0-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group, whilst in the abovementioned groups A to D R 4 to R 10 are as hereinbefore defined,
  • R a denotes a hydrogen atom
  • R b denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst
  • R x and R 2 which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
  • R 3 denotes a hydrogen, fluorine, chlorine or bromine atom
  • R c and R d in each case denote a hydrogen atom
  • X denotes a nitrogen atom
  • A denotes an -0-C 1-4 -alkylene , -0-C 4 . 7 -cycloalkylene , -O-C ⁇ - j -al- kylene-C 3-7 -cycloalkylene , -0-C 4 . 7 -cycloalkylene-C 1 . 3 -alkylene or -0-C 1.3 -alkylene-C 3-7 -cycloalkylene-C 1 . 3 -alkylene group , whilst the oxygen atom of the abovementioned groups in each 'case is linked to the bicyclic heteroaromatic ring,
  • R 6 0-CO-alkylene-NR 5 (R 7 0-PO-OR 8 ) -alkylene-NR s or (R 7 0-PO-R 9 ) -alkylene-NR s group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 4 carbon atoms, may additionally be substituted by one or two C ⁇ -alkyl groups or by an R 6 0-CO or group, whilst
  • R 5 denotes a hydrogen atom
  • R 6 , R 7 and R 8 which may be identical or different, in each case denote a hydrogen atom
  • a C ⁇ -alkyl group which may be substituted from position 2 onwards by a hydroxy, C ⁇ -alkoxy or di- (C 1-4 -alkyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen atom or by an N- (C ⁇ -alkyl) -imino group, a C 4 . 6 -cycloalkyl group,
  • R e and R f which may be identical or different, in each case denote a hydrogen atom or a C ⁇ -alkyl group and
  • R g denotes a C ⁇ -alkyl, C 3 . 6 -cycloalkyl, C ⁇ -alkoxy or C s . 6 -cycloalkoxy group,
  • R 9 denotes a C ⁇ -alkyl group
  • R 10 denotes a hydrogen atom, a methyl or ethyl group
  • a piperazino or homopiperazino group which is substituted in the 4 position by the group R 10 and is additionally substituted at cyclic carbon atoms by two RgO-CO or RgO-CO-C 1-4 -alkyl groups wherein R 6 and R 10 are as hereinbefore defined, a piperazino or homopiperazino group which in each case is substituted in the 4 position by an R 6 0-CO-C 1-4 -alkyl, bis- (RgO-CO) -C ⁇ -alkyl, (R 7 0-PO-OR 8 ) -C ⁇ -alkyl or (R 7 0-PO-R 9 ) - C ⁇ -alkyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R s is as hereinbefore defined and
  • R xx denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydro- furan-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydro- pyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two methyl groups,
  • a C 2 . 4 -alkoxy group which is substituted from position 2 by a hydroxy, C 1-4 -alkoxy, amino, C ⁇ -alkylamino, di- (C ⁇ -alkyl) - amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C ⁇ -alkyl) -piperazino group,
  • C denotes an -0-C 1 . 4 -alkylene, -0-C 4-7 -cycloalkylene, -O-Ci. 3 -alkylene-C 3-7 -cycloalkylene, -0-C 4 . 7 -cyclo- alkylene-C ⁇ -alkylene or -0-C 1 . 3 -alkylene-C 3 . 7 -cycloal- kylene-C 1-3 -alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
  • D denotes an R 6 0-CO-alkylene-NR 5 , (R 7 0-PO-OR 8 ) -alkylene-NR s or (R 7 0-PO-R 9 ) -alkylene-NR 5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 4 carbon atoms, may additionally be substituted by one or two C 1 . 2 -alkyl groups or by an R 6 0-C0 or group, whilst R 5 to R 9 are as hereinbefore defined,
  • R 6 a 4- to 7-membered alkyleneimino group which is substituted by an R g O-CO, R 6 0-CO-C 1-4 -alkyl or bis- (R 6 0-CO) -C ⁇ -alkyl group wherein R 6 is as hereinbefore defined,
  • R n NR 5 group wherein R 5 and R x are as hereinbefore defined, or
  • a C 2 . 4 -alkoxy group which is substituted from position 2 by a hydroxy, C ⁇ -alkoxy, amino, C ⁇ -alkylamino, di- (C ⁇ -alkyl) - amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C ⁇ -alkyl) -piperazino group, a C 1-4 -alkoxy group which is substituted by a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R 10 , whilst R 10 is as hereinbefore defined,
  • At least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R 7 0-PO-OR 8 ) or (R 7 0-PO- R 9 ) group, or
  • At least one of the groups B or D contains an optionally substituted 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran- 4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group, or
  • At least one of the groups A, B, C or D or A together with B or C together with D contains an R 6 0-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
  • aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which in each case may be monosubstituted by R 12 , mono- or disubstituted by R 13 or monosubstituted by R 12 and additionally mono- or disubstituted by R 13 , whilst the substituents may be identical or different and
  • R 12 denotes a cyano, C ⁇ -alkoxycarbonyl, aminocarbonyl , C ⁇ -alkylaminocarbonyl, di- (C ⁇ -alkyl) -aminocarbonyl, C 1-2 -alkylsulphenyl, C ⁇ -alkylsulphinyl, C ⁇ -alkylsulphonyl, hydroxy, nitro, amino, C 1 . 4 -alkylamino or di- (C ⁇ -alkyl) -amino group and
  • R 13 denotes a fluorine, chlorine, bromine or iodine atom, a Ci.j-alkyl, trifluoromethyl or C 1 . 2 -alkoxy group or
  • R a denotes a hydrogen atom
  • R b denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst
  • R x and R 2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
  • R 3 denotes a hydrogen atom
  • R c and R d in each case denote a hydrogen atom
  • X denotes a nitrogen atom
  • A denotes an -0-C 1-4 -alkylene or -0-CH 2 -CH (OH) -CH 2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring
  • B denotes an R 6 0-CO-alkylene-NR 5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R 6 0-CO or R 6 0-CO- methyl group, whilst
  • R 5 denotes a hydrogen atom
  • R e denotes a hydrogen atom
  • R e denotes a hydrogen atom or a C ⁇ -alkyl group
  • R f denotes a hydrogen atom
  • R g denotes a C 1 . 4 -alkyl, cyclopentyl, cyclohexyl, C ⁇ -alkoxy, cyclopentyloxy or cyclohexyloxy group,
  • a pyrrolidino or piperidino group which is substituted by two R g O-CO or R g O-CO-C 1-2 -alkyl groups wherein R 6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by the group R 10 and additionally at a cyclic carbon atom by an RgO-CO or group wherein R 6 is as hereinbefore defined and
  • R 10 denotes a hydrogen atom, a methyl or ethyl group
  • R 7 and R 8 which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or R g CO-0- (R e CR f ) group, whilst
  • R e to R g are as hereinbefore defined,
  • R 9 denotes a methyl or ethyl group
  • R 6 0-CO-C 1-4 -alkyl bis- (R 6 0-CO) -C 1-4 -alkyl, (R 7 0-PO-OR 8 ) -methyl or (R 7 0-PO-R 9 ) -methyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R 11 N(C 1 . 2 -alkyl) group wherein R xx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, or
  • a and B together denote a hydrogen atom, a methoxy, ethoxy or 2-methoxy-ethoxy group,
  • C denotes an -O-C ⁇ -alkylene or -0-CH 2 -CH (OH) -CH 2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
  • D denotes an R 6 0-CO-alkylene-NR 5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R 6 0-CO or R 6 0-CO- methyl group, whilst R 5 and R 6 are as hereinbefore defined,
  • R X1 denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, or
  • C and D together denote a hydrogen atom, a methoxy, ethoxy or 2-methoxy-ethoxy group,
  • At least one of the groups A, B, C or D or A together with B or C together with D contains an R 6 0-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
  • R a denotes a hydrogen atom
  • R b denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst
  • R x and R 2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
  • R 3 denotes a hydrogen atom
  • R c and R d in each case denote a hydrogen atom
  • X denotes a nitrogen atom
  • A denotes an -O-C ⁇ -alkylene or -0-CH 2 -CH (OH) -CH 2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
  • R 6 0-CO-alkylene-NR s group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R 6 0-CO or R 6 0-CO- methyl group, whilst
  • R 5 denotes a hydrogen atom
  • R 6 denotes a hydrogen atom
  • R e denotes a hydrogen atom or a C ⁇ -alkyl group
  • R f denotes a hydrogen atom
  • R g denotes a C ⁇ -alkyl, cyclopentyl, cyclohexyl, C ⁇ -alkoxy, cyclopentyloxy or cyclohexyloxy group,
  • a pyrrolidino or piperidino group which is substituted by an R g O-CO or R g O-CO-C 1-2 -alkyl group wherein R 6 is as hereinbefore defined
  • a pyrrolidino or piperidino group which is substituted by two RgO-CO or RgO-CO-Ci.j-alkyl groups wherein R 6 is as hereinbefore defined
  • R 10 denotes a hydrogen atom, a methyl or ethyl group
  • R 7 and R 8 which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or R g CO-0- (R e CR f ) group, whilst
  • R e to R g are as hereinbefore defined,
  • R 9 denotes a methyl or ethyl group
  • R 6 to R 9 are as hereinbefore defined, a 2-oxo-morpholino group which may be substituted by '1 or 2 methyl groups,
  • R X1 denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group
  • C and D together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C 4 . 6 -cycloalkoxy or C 3 .g-cycloalkyl-C 1 . 3 -alkoxy group,
  • R a denotes a hydrogen atom
  • R b denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst
  • R and R 2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
  • R 3 denotes a hydrogen atom
  • R c and R d in each case denote a hydrogen atom
  • X denotes a nitrogen atom
  • a and B together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C 4 . 6 -cycloalkoxy or C 3 . 6 -cycloalkyl-C 1 . 3 -alkoxy group,
  • C denotes an -O-C ⁇ -alkylene or -0-CH 2 -CH (OH) -CH 2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, and
  • D denotes an R 6 0-CO-alkylene-NR 5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R 6 0-CO or R ⁇ O-CO- methyl group, whilst
  • R s denotes a hydrogen atom
  • R 6 denotes a hydrogen atom
  • R e denotes a hydrogen atom or a C 1-4 -alkyl group
  • R f denotes a hydrogen atom
  • R g denotes a C ⁇ -alkyl, cyclopentyl, cyclohexyl, C ⁇ -alkoxy, cyclopentyloxy or cyclohexyloxy group, a pyrrolidino or piperidino group which is substituted by an RgO-CO or group wherein R 6 is as hereinbefore defined,
  • R 10 denotes a hydrogen atom, a methyl or ethyl group
  • R 7 and R 8 which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or R g CO-0- (R e CR f ) group, whilst
  • R e to R g are as hereinbefore defined,
  • R 9 denotes a methyl or ethyl group
  • R 6 to R 9 a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R g O-CO-C ⁇ -alkyl, bis- (R 6 0-CO) -C ⁇ -alkyl , (R 7 0-PO-OR 8 ) -methyl or (R 7 0-PO-R 9 ) -methyl group wherein R 6 to R 9 are as hereinbefore defined,
  • R xx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group
  • bicyclic heterocyclic compounds of general formula I are those wherein
  • R a denotes a hydrogen atom
  • R b denotes a phenyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst
  • R x and R 2 which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and
  • R 3 denotes a hydrogen atom
  • R c and R d in each case denote a hydrogen atom
  • X denotes a nitrogen atom
  • A denotes an -O-C ⁇ -alkylene or -0-CH 2 -CH (OH) -CH 2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
  • B denotes an R 6 0-CO-CH 2 -NR 5 group wherein
  • R 5 denotes a hydrogen atom or a methyl group which may be substituted by an R 6 0-CO group, or
  • R 6 denotes a hydrogen atom, a methyl or ethyl group
  • R 11 N(C 1-2 -alkyl) group wherein R xx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, and
  • C and D together denote a methoxy, C 4 . s -cycloalkoxy or C 3 . 6 -cycloalkylmethoxy group,
  • R a denotes a hydrogen atom
  • R b denotes a phenyl group wherein the phenyl nucleus is substituted in each case by the groups R x to R 3 , whilst R x and R 2 , which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and
  • R 3 denotes a hydrogen atom
  • R c and R d in each case denote a hydrogen atom
  • X denotes a nitrogen atom
  • a and B together denote a C 4 . 6 -cycloalkoxy or C 3 . 6 -cycloalkyl- methoxy group
  • C denotes an -0-CH 2 CH 2 group, whilst the oxygen atom of the abovementioned group is linked to the bicyclic heteroaromatic ring,
  • D denotes an R 6 0-CO-CH 2 -NR 5 group
  • R s denotes a C 2 . 4 -alkyl group substituted from position 2 onwards by a hydroxy group
  • R 6 denotes a methyl or ethyl group
  • R 11 N(C 1 . 2 -alkyl) group wherein R xx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
  • the compounds of general formula I may, for example, be prepared by the following methods :
  • R a to R d , C, D and X are as hereinbefore defined and
  • A' denotes one of the optionally substituted alkylene, cycloal- kylene, alkylene-cycloalkylene, cycloalkylene-alkylene or alkylene-cycloalkylene-alkylene moieties mentioned above for the group A, which are linked to the heteroaromatic group via an oxygen atom or via an NR 4 group, and
  • Z denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group.
  • the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chloroben- zene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (H ⁇ nig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150 °C.
  • solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluen
  • R a to R d , A, B and X are as hereinbefore defined and denotes an oxygen atom or an R 4 N group, whilst R 4 is as hereinbefore defined, with a compound of general formula Z 2 - C - D , (V)
  • C denotes one of the optionally substituted alkylene, cycloal- kylene, alkylene-cycloalkylene, cycloalkylene-alkylene or alkylene-cycloalkylene-alkylene moieties mentioned above for the group C, which are linked to the heteroaromatic group via an oxygen atom or via an NR 4 group, and
  • Z 2 denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group.
  • the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chloroben- zene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (Hunig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of an alkali or alkaline earth metal alkoxide such as sodium ethoxide or potassium tert .butoxide conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
  • solvents
  • R a to R d , C, D and X are as hereinbefore defined and
  • A" has the meanings given for A hereinbefore with the exception of the oxygen atom and the -NR 4 group and
  • Z 3 denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group or together with a hydrogen atom of an adjacent hydrocarbon group denotes an oxygen atom, with a compound of general formula
  • the reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, ethanol, methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydro- furan or dioxane, optionally in the presence of a tertiary organic base such as triethylamine, pyridine or 2 -dimethyl- aminopyridine , in the presence of N-ethyl-diisopropylamine (H ⁇ nig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of an alkali or alkaline earth metal alkoxide such as sodium ethoxide or potassium tert.but- oxide, conveniently at temperatures between -20 and 200°C, preferably at
  • Z 4 denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group or together with a hydrogen atom of an adjacent hydrocarbon group denotes an oxygen atom, with a compound of general formula
  • the reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, ethanol, .methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydro- furan or dioxane optionally in the presence of a tertiary organic base such as triethylamine, pyridine or 2 -dimethyl- aminopyridine, in the presence of N-ethyl-diisopropylamine (H ⁇ nig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of an alkali or alkaline 'earth metal alkoxide such as sodium ethoxide or potassium tert.but- oxide, conveniently at temperatures between -20 and 200°C,
  • R a to R d , A, C, D and X are as hereinbefore defined and
  • B' denotes an R 5 NH group wherein R 5 is as hereinbefore defined, a piperazino or homopiperazino group unsubstituted in the 4 position, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group unsubstituted in the 1 position, with a compound of general formula
  • a halogen atom or a substituted sulphonyloxy group e.g. a chlorine or bromine atom, a methylsulphonyloxy, propylsulphonyloxy, phenylsulphonyloxy or benzylsulphony
  • the reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethyl- formamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (H ⁇ nig's base) , whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
  • solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethyl- formamide, dimethylsulphoxide, sulpholane, benzene, toluen
  • R a to R d , A to C and X are as hereinbefore defined and
  • D' denotes an R 5 NH group wherein R 5 is as hereinbefore defined, a piperazino or homopiperazino group unsubstituted in the 4 position, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group unsubstituted in the 1 position, with a compound of general formula
  • alkylene moiety which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two group, whilst R 6 in each case is. as hereinbefore defined, and
  • Z 5 denotes an exchangeable group such as a halogen atom or a substituted sulphonyloxy group, e.g. a chlorine or bromine atom, a methylsulphonyloxy, propylsulphonyloxy, phenylsulpho- nyloxy or benzylsulphonyloxy group.
  • the reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethyl- formamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (H ⁇ nig's base) , whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
  • solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethyl- formamide, dimethylsulphoxide, sulpholane, benzene, toluen
  • R a to R d , A, C and X are as hereinbefore defined,
  • B" and D have the meanings given for B and D hereinbefore, with the proviso that at least one of the groups B" or D" contains an R 6 0-CO, (R 7 0-PO-OR 8 ) or (R 7 0-PO-R 9 ) group wherein R 9 is as hereinbefore defined and at least one of the groups R 6 to
  • R 8 does not represent a hydrogen atom, by hydrolysis, treating with acids, thermolysis or hydrogenolysis, into a compound of general formula I wherein at least one of the groups R s to R 8 denotes a hydrogen atom.
  • the hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoro- acetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol , water/ethanol, water/isopropanol , methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
  • an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoro- acetic acid or mixtures thereof
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a suitable solvent such as water, water/methanol
  • the tert.butyl group may also be cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120°C, e.g.
  • an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid
  • an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120°C,
  • any N-tert .butyloxycarbonylamino or N-tert .butyloxycarbonylimino groups present may be converted into the corresponding amino or imino groups .
  • the benzyl group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
  • a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
  • a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethy
  • a nitro group may be converted into an amino group, a benzyloxy group into a hydroxy group and a N-benzylamino, N-benzylimino, N-benzyloxycarbonyl- amino or N-benzyloxycarbonylimino group into a corresponding amino or imino group .
  • the subsequent esterification is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or particularly advantageously in a corresponding alcohol, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g.
  • the subsequent ester formation may also be carried out by reacting a compound which contains a carboxy or hydroxy- phosphoryl group with a corresponding alkyl halide.
  • the subsequent intramolecular cyclisation is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, tetrahydrofuran, dioxane or toluene in the presence an acid such as hydrochloric acid or p-toluenesulphonic acid at temperatures between -10 and 120°C.
  • a solvent or mixture of solvents such as acetonitrile, methylene chloride, tetrahydrofuran, dioxane or toluene
  • an acid such as hydrochloric acid or p-toluenesulphonic acid at temperatures between -10 and 120°C.
  • any reactive groups present such as hydroxy, carboxy, phosphono, O-alkyl-phosphono, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,-
  • protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group,
  • protecting groups for a phosphono group may be an alkyl group such as the methyl, ethyl, isopropyl or n-butyl group, the phenyl or benzyl group, and
  • protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.but- oxycarbonyl, benzyloxycarbonyl, benzyl , methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group .
  • Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroace- tic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.
  • an aqueous solvent e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroace- tic acid, hydrochloric acid or sulphuric acid or in the
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
  • a 2, 4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol.
  • a tert.butyl or tert .butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
  • a trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.
  • an acid such as hydrochloric acid
  • a solvent such as acetic acid at temperatures between 50 and 120°C
  • sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.
  • a phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, iso- propanol, toluene/water or dioxane at temperatures between 20 and 50°C.
  • a single alkyl group may be cleaved from an 0,0' -dialkylphos- phono group with sodium iodide, for example, in a solvent such as acetone, methylethylketone, acetonitrile or dimethylform- amide at temperatures between 40 and 150°C, but preferably at temperatures between 60 and 100°C.
  • a solvent such as acetone, methylethylketone, acetonitrile or dimethylform- amide
  • Both alkyl groups may be cleaved from an 0,0' -dialkyl-phos- phono group with iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane/sodium iodide, for example, in a solvent such as methylene chloride, chloroform or acetonitrile at temperatures between 0°C and the boiling temperature of the reaction mixture, but preferably at temperatures between 20 and 60°C.
  • the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore.
  • cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
  • the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as race- mates may be separated by methods known per se (cf . Allinger
  • the enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • Optically active acids in common use are e.g.
  • An optically active alcohol may be for example ⁇ +) or (-) -menthol and an optically active acyl group in amides, for example, may be a (+)-or ( - ) -menthyloxycarbonyl .
  • the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained contain a carboxy, hydroxyphosphoryl , sulpho or 5-tetrazolyl group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof .
  • Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexyl- amine, ethanolamine, diethanolamine and triethanolamine .
  • the compounds of general formulae II to XIII used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf . Examples I to XVI) .
  • the compounds of general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R) , whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible to block the transmission of signals to components located further down.
  • EGF-R Epidermal Growth Factor receptor
  • the biological properties of the new compounds were investigated as follows: The inhibition of the EGF-R-mediated signal transmission can be demonstrated e.g. with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha.
  • a cell line of murine origin dependent on interleukin-3- (IL-3) which was genetically modified to express functional human EGF-R was used here.
  • the proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf . von R ⁇ den, T. et al . in EMBO J. 2, 2749-2756 (1988) and Pierce, J. H. et al . in Science 2.19., 628-631 (1988)).
  • the starting material used for the F/L-HERc cells was the cell line FDC-Pi, the production of which has been described by Dexter, T. M. et al . in J. Exp. Med. 152 r 1036-1047 (1980).
  • other growth-factor-dependent cells may also be used (cf. for example Pierce, J. H. et al . in Science 223., 628-631 (1988), Shibuya, H. et al . in Cell _7_Q, 57-67 (1992) and Alexander, W. S. et al . in EMBO J. ID., 3683- 3691 (1991)).
  • human EGF-R cDNA cf. Ullrich, A.
  • retroviral vector LXSN cf. Miller, A. D. et al . in BioTechniques 1, 980-990 (1989)
  • LXSN cf. Miller, A. D. et al . in BioTechniques 1, 980-990 (1989)
  • the line GP+E86 cf. Markowitz, D. et al. in J. Virol. £L2., 1120- 1124 (1988) was used as the packaging cell.
  • F/L-HERc cells were cultivated in RPMl/1640 medium (BioWhittaker) , supplemented with 10 % foetal calf serum (FCS, Boehringer Mannheim) , 2 mM glutamine (BioWhittaker) , standard antibiotics and 20 ng/ml of human EGF (Promega) , at 37°C and 5% CO2.
  • F/L-HERc cells were cultivated in RPMl/1640 medium (BioWhittaker) , supplemented with 10 % foetal calf serum (FCS, Boehringer Mannheim) , 2 mM glutamine (BioWhittaker) , standard antibiotics and 20 ng/ml of human EGF (Promega) , at 37°C and 5% CO2.
  • F/L-HERc cells were cultivated in RPMl/1640 medium (BioWhittaker) , supplemented with 10 % foetal calf serum (FCS, Boehringer Mannheim) , 2 mM
  • the IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. Karasuyama, H. et al . in Eur. J. Immunol. IR, 97-104 (1988) ) .
  • the compounds according to the invention were dissolved in 100% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37°C.
  • DMSO dimethylsulphoxide
  • the relative cell number was measured in O.D. units using the Cell Titer 96TM AQ ue ⁇ us Non- Radioactive Cell Proliferation Assay (Promega) .
  • the relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC5 0 ) was derived therefrom. The following results were obtained:
  • the compounds of general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosinekinases .
  • tyrosine kinases e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoan- giogenesis) .
  • the compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosinekinases ' , e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiecta- sias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ l-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
  • inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiecta- sias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ l-antitrypsin deficiency, or coughs, pulmonary emphys
  • the compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosinekinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn” s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Menetrier's disease, secreting adenomas and protein loss syndrome, and also for treating nasal polyps and polyps of the gastrointestinal tract of various origins such as e.g.
  • villous or adenomatous polyps of the large bowel but also polyps in familial polyposis coli, intestinal polyps in Gardner's syndrome, polyps throughout the entire gastrointestinal tract in Koz-Jeghers syndrome, in inflammatory pseudopolyps, juvenile polyps, Colitis cystica profunda and Pneumatosis cystoides intestinales .
  • the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly in cystic changes such as cystic kid- neys, for treating renal cysts which may be idiopathic in origin or occur in syndromes such as e.g. tuberculous sclerosis, in von-Hippel-Lindau Syndrome, in nephronophthisis and spongy kidney and other diseases caused by aberrant function of tyrosinekinases, such as e.g. epidermal hyperproliferation (psoriasis) , inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, etc.
  • kidney diseases particularly in cystic changes such as cystic kid- neys
  • renal cysts which may be idiopathic in origin or occur in syndromes such as e.g. tuberculous sclerosis, in von-Hippel-Lindau Syndrome, in nephronophthisis and spongy kidney and other diseases caused
  • the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide) , mitosis inhibitors (e.g. vinblastin) , compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adria- mycin) , hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc.
  • topoisomerase inhibitors e.g. etoposide
  • mitosis inhibitors e.g. vinblastin
  • nucleic acids e.g. cis-platin, cyclophosphamide, adria- mycin
  • hormone antagonists
  • these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti- inflammatory activity.
  • these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion or antiinflammatory substances. These combinations may be administered either simultaneously or sequentially.
  • these compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intrarectal, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
  • the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg.
  • they are formulated with one or more conventional inert carriers and/or diluents, e.g.
  • reaction mixture is then left to cool .
  • the precipitate formed is suction filtered, washed thoroughly with cold iso- propanol and dried.
  • 1 tablet core contains : active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1 ⁇ mg
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate.
  • Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet- making machine to form tablets of the desired shape.
  • the tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose.
  • the finished film-coated tablets are polished with beeswax. Weight of coated tablet: 245 mg.
  • 1 tablet contains : active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg
  • the active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets .
  • Diameter 10 mm, biplanar, facetted on both sides and notched on one side.
  • 1 tablet contains : active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate l.Q g
  • the active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm.
  • the granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
  • 1 capsule contains : active substance 150.0 mg corn starch (dried approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3,0 mg approx. 420.0 mg Preparation;
  • the active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • Capsule shell size 1 hard gelatine capsule.
  • 1 suppository contains : active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg
  • the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
  • 100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g
  • the distilled water is heated to 70°C.
  • the methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring.
  • the solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
  • the suspension is evacuated with stirring to eliminate air.
  • 5 ml of suspension contain 50 mg of active substance.
  • composition active substance 10.0 mg
  • the active substance is dissolved in the necessary amount of 0.01 N HC1, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
  • composition active substance 50.0 mg
  • the active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
  • 1 capsule contains :
  • the active substance is mixed with lactose for inhalation.
  • the mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg) .
  • 1 spray contains :
  • the active substance and benzalkonium chloride are dissolved in ethanol/water (50/50) .
  • the pH of the solution is adjusted with IN hydrochloric acid.
  • the resulting solution is filtered and transferred into suitable containers for use in hand-held nebulisers (cartridges) .

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Abstract

The present invention relates to bicyclic heterocyclic compounds of general formula (I), wherein Ra to Rd, A to D and X are defined as in claims 1 to 8, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in treating diseases, particularly tumour diseases, diseases of the lung and airways and the preparation thereof.

Description

BICYCLIC HETEROCYCLES, PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS , AND PROCESSES FOR PREPARING THEM
The present invention relates to bicyclic heterocyclic compounds of general formula
Figure imgf000003_0001
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on the signal transduction mediated by tyrosine kinases, their use in treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract and the preparation thereof.
In the above general formula I
Ra denotes a hydrogen atom or a C1.4-alkyl group,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
R-L and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a C^-alkyl, hydroxy, C^-alkoxy, C3.6-cycloalkyl, C4.6-cycloalkoxy, C2-5-alkenyl or C2.5-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group,
a C3.s-alkenyloxy or C3.5-alkynyloxy group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C1.4-alkylsulphenyl, C^-alkylsulphinyl, C1.4-alkylsulpho- nyl, C^-alkylsulphonyloxy, trifluoromethylsulphenyl, tri- fluoromethylsulphinyl or trifluoro ethylsulphonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a cyano or nitro group or an amino group optionally substituted by one or two C^-alkyl groups, whilst the substituents may be identical or different,
or R-L together with R2, if they are bound to adjacent carbon atoms, denote a -CH=CH-CH=CH, -CH=CH-NH or -CH=N-NH group and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
a C^-alkyl, trifluoromethyl or C1-4-alkoxy group,
Rc and Rd, which may be identical or different, each denote a hydrogen, fluorine or chlorine atom, a methoxy group or a methyl group optionally substituted by a methoxy, dimethyl- amino, diethylamino, pyrrolidino, piperidino or morpholino group,
X denotes a methine group substituted by a cyano group or a nitrogen atom, A denotes an -0-C1.6-alkylene, -0-C4.7-cycloalkylene, -O-CJL.3-alkylene-C3.7-cycloalkylene, -0-C4_7-cyclo- alkylene-C1-3-alkylene or -0-C1.3-alkylene-C3.7-cycloal- kylene-C^-alkylene group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
an -0-C1-6-alkylene group which is substituted by an R60-CO or R60-CO-C1-4-alkyl group, whilst R6 is as hereinafter defined and the oxygen atom of the abovementioned -O-C^-alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
an -0-C2.6-alkylene group which is substituted from position 2 onwards by a hydroxy, C-^-alkoxy, amino, C1-4-alkylamino, di- (C1.4-alkyl) -amino, pyrrolidino, piperidino, morpholino, pipera- zino or 4- (C1-4-alkyl) -piperazino group and the oxygen atom of the abovementioned-0-C2.s-alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
a -C-..5-alkylene group,
an -NR4-C1.6-alkylene, -NR4-C3.7-cycloalkylene, -NR4-C^-alkylene- C3.7-cycloalkylene, -NR4-C3.7-cycloalkylene-C1.3-alkylene or -NR4-C1_3-alkylene-C3.7-cycloalkylene-C1_3-alkylene group, whilst the -NR4- moiety of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, and
R4 denotes a hydrogen atom or a C1.4-alkyl group,
an oxygen atom, this being linked to a carbon atom of the group B, or
a NR4 group, the latter being linked to a carbon atom of the group B and R4 being as hereinbefore defined,
B denotes an R60-CO-alkylene-NRs, (R70-PO-OR8) -alkylene-NR5 or (R70-PO-R9) -alkylene-NRs group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C1.2-alkyl groups or by an R60-C0 or
Figure imgf000006_0001
group, whilst
R5 denotes a hydrogen atom,
a C^-alkyl group which may be substituted by an R60-CO, (R70-PO-OR8) or (R70-PO-R9) group,
a C2.4-alkyl group which is substituted from position 2 by a hydroxy, C1.4-alkoxy, amino, C1.4-alkylamino or di- (C1.4-al- kyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C1.4-alkyl) -imino group,
a C3.7-cycloalkyl or C3-7-cycloalkyl-C1_3-alkyl group,
R6, R7 and R8, which may be identical or different, in each case denote a hydrogen atom,
a Ci.g-alkyl group which may be substituted from position 2 onwards by a hydroxy, C^-alkoxy, amino, C^-alkylamino or di- (C^-alkyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C^-alkyl) - imino group,
a C4.7-cycloalkyl group optionally substituted by 1 or 2 methyl groups ,
a C3.s-alkenyl or C3-s-alkynyl group, whilst the unsaturated moiety may not be linked to the oxygen atom, a C3.7-cycloalkyl-C1.4-alkyl, aryl, aryl-C^-alky1 or RgCO-0- (ReCRf) group, whilst
Re and Rf, which may be identical or different, in each case denote a hydrogen atom or a C1.4-alkyl group and
Rg denotes a C1.4-alkyl, C3-7-cycloalkyl, C1-4-alkoxy or C5-7-cycloalkoxy group,
and R9 denotes a C^-alkyl, aryl or aryl-C^,,-alky1 group,
a 4- to 7-membered alkyleneimino group which is substituted by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) ,
Figure imgf000007_0001
bis- (R60-CO) -C1.4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two R60-CO or
Figure imgf000007_0002
groups or by an R6OCO group and an R60-CO-C1_4-alkyl group wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO- C1-4-alkyl, bis- (R60-CO) -C^-alkyl , (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R9 are as hereinbefore defined and
R10 denotes a hydrogen atom, a C1.4-alkyl, formyl, C1.4-alkylcarbonyl or C1.4-alkylsulphonyl group,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or R60-CO-Cx.4-alkyl groups or by an R60-CO group and an
Figure imgf000007_0003
group wherein R6 and R10 are as hereinbefore defined, a piperazino or homopiperazino group which is substituted in each case in the 4 position by an
Figure imgf000008_0001
bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an
Figure imgf000008_0002
(R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C1.4-alkyl group and is additionally substituted at cyclic carbon atoms by one or two RgO-CO or R60-CO-C1.4-alkyl groups or by an R60-CO group and an R60-CO-C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a orpholino or homomorpholino group which is substituted in each case by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) ,
Figure imgf000008_0003
kyl, bis- (R60-CO) -C1-4-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or
Figure imgf000008_0004
groups or by an R60-CO group and an RgO-CO-C^-alkyl group wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5 to 7-membered rings are in each case additionally substituted at a carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , RgO-CO-C^-alkyl, bis- (R60-CO) -C1.4-alkyl, (R70-PO-OR8) -C1.4-alkyl or (R70-PO-R9) -Cx.4-alkyl group wherein R6 to R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5 to 7-membered rings in each case are additionally substituted at carbon atoms by two R60-CO or R60-CO-C1.4-alkyl groups or by an R60-CO group and an
Figure imgf000008_0005
group wherein R6 and R10 are as hereinbefore defined, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000009_0001
bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000009_0002
bis- (R60-CO) - C1-4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at carbon atoms by one or two RgO-CO or RgO-CO-C1„4-alkyl groups or by an R60-CO group and an
Figure imgf000009_0003
group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 C1-2-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a
Figure imgf000009_0004
(R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -Cx.4-alkyl group, whilst R6 to R9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups in each case are linked to a carbon atom of the group A,
an R1:1NR5 group wherein R5 is as hereinbefore defined and
RX1 denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahy- drofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahy- dropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two methyl groups,
or A and B together denotes a hydrogen, fluorine or chlorine atom,
a Ci.g-alkoxy group, a C2.6-alkoxy group which is substituted from position 2 onwards by a hydroxy, C1-4-alkoxy, amino, C1.4-alkylamino, di- (C^-al- kyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C1.4-alkyl) -piperazino, homopiperazino, 4- (C^-alkyl) -homopiperazino or 1-imidazolyl group,
a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined,
a
Figure imgf000010_0001
group which is substituted by an R60-CO, (R70-PO-OR8) or (R70-PO-R9) group, whilst R6 to R9 are as hereinbefore defined,
a C3.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group,
an amino, C1.4-alkylamino, di- (C^-alkyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino or 4- (C^-alkyl) -homopiperazino group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
C denotes an -0-C1-6-alkylene, -0-C4.7-cycloalkylene, -D-C^-al- kylene-C3.7-cycloalkylene, -0-C4-7-cycloalkylene-C1-3-alkylene or -0-C1.3-alkylene-C3.7-cycloalkylene-C1-3-alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
an -O-Ci.g-alkylene group which is substituted by an R60-C0 or RjO-CO-C^-alkyl group, whilst R6 is as hereinbefore defined and the oxygen atom of the groups in each case is linked to the bicyclic heteroaromatic ring, an -0-C2.6-alkylene group which is substituted from position 2 by a hydroxy, C^-alkoxy, amino, C^-alkylamino, di- (C1.4-al- kyl) -amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C^-alkyl) -piperazino group and the oxygen atom of the abovementioned-0-C2.s-alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
a -Cx_6-alkylene group,
an -NR4-C1.6-alkylene, -NR4-C3_7-cycloalkylene, -NR4-C1.3-alkylene- C3-7-cycloalkylene, -NR4-C3-7-cycloalkylene-C1.3-alkylene or -NR4-C1.3-alkylene-C3.7-cycloalkylene-C1.3-alkylene group, whilst the -NR4- moiety of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring and R4 is as hereinbefore defined,
an oxygen atom, which is linked to a carbon atom of the group D, or
a NR4 group, where the latter is linked to a carbon atom of the group D and R4 is as hereinbefore defined,
D denotes an R60-CO-alkylene-NR5, (R70-PO-OR8) -alkylene-NR5 or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or
Figure imgf000011_0001
group, whilst R5 to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO-C1-4-alkyl , bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -Cx.4-al yl or (R70-PO-R9) - C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two RgO-CO or R60-CO-C1-4-alkyl groups or by an R6OCO group and an R60-CO-C1-4-alkyl group wherein R6 is as hereinbefore defined, a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO- C1-4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R1Q are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or R60-CO-C1.4-alkyl groups or by an R60-CO group and an
Figure imgf000012_0001
group wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in each case in the 4 position by an RgO-CO-Cx.4-alkyl, bis- (RgO-CO) -C1-4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an
Figure imgf000012_0002
, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C1-4-alkyl group and is additionally substituted at cyclic carbon atoms by one or two RgO-CO or R60-CO-C1-4-alkyl groups or by an R60-CO group and an R60-CO-C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a morpholino or homomorpholino group which is substituted in each case by an R60-C0, (R70-PO-OR8) , (R70-PO-R9) , RgO-CO- C^-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or R60-CO-C1-4-alkyl groups or by an R60-CO group and an RgO-CO-C^-alkyl group wherein R6 is as hereinbefore defined, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-C0, (R70-P0-0R8) , (R70-P0-R9) , R60-CO-C1.4-alkyl, bis- (RsO-CO) -C1-4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by two R60-CO or
Figure imgf000013_0001
groups or by an R60-C0 group and an
Figure imgf000013_0002
group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C1.4-alkyl, bis- (RsO-CO) - C1-4-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000013_0003
bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by one or two RgO-CO or R60-CO-C1-4-alkyl groups or by an R60-CO group and an
Figure imgf000013_0004
group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 Ci.j-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a C^-alkyl, RgO-CO-C1-4-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -Cx.4-alkyl group, whilst R6 to R9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups are in each case linked to a carbon atom of the group C,
an R1XNR5 group wherein Rs and Rxl are as hereinbefore defined, or
C and D together denote a hydrogen, fluorine or chlorine atom,
a Ci.g-alkoxy group,
a C2.6-alkoxy group which is substituted from position 2 by a hydroxy, C^-alkoxy, amino, C^-alkylamino, di- (C1.4-alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C1.4-alkyl) -piperazino, homopiperazino, 4- (C^-alkyl) -homopiperazino or 1-imidazolyl group,
a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined,
a
Figure imgf000014_0001
group which is substituted by an RgO-CO, (R70-PO- 0R8) or (R70-PO-R9) group, whilst R6 to R9 are as hereinbefore defined,
a C3.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group
an amino, C1-4-alkylamino, di- (C1-4- lkyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino or 4- (C^-al- kyl) -homopiperazino group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups ,
with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, an (R70-PO-OR8) or (R70-PO- R9) group, or
that at least one of the groups B or D contains an optionally substituted 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran- 4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group, or
that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group.
By the aryl moieties mentioned in the definition of the above- mentioned groups is meant a phenyl group which may in each case be monosubstituted by R12, mono-, di- or trisubstituted by R13 or monosubstituted by R12 and additionally mono- or disub- stituted by R13, whilst the substituents may be identical or different and
R12 denotes a cyano, carboxy, C^-alkoxycarbonyl, aminocarbo- nyl, C^-alkylaminocarbonyl, di- (C^-alkyl) -aminocarbonyl, C^-alkylsulphenyl, C1-4-alkylsulphinyl, Cτ_4-alky1sulphonyl, hydroxy, C1.4-alkylsulphonyloxy, trifluoromethyloxy, nitro, amino, C^-alkylamino, di- (C^-alkyl) -amino, C^-alkyl- carbonylamino, N- (C^-alkyl) -C^-alkylcarbonylamino, C-^-al- kylsulphonylamino, N- (C^-alkyl) -C1.4-alkylsulphonylamino, aminosulphonyl , C1-4-alkylaminosulphonyl or di- (C1.4-alkyl) - aminosulphonyl group or a carbonyl group which is substituted by a 5- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C1.4-alkyl) -imino group, and R13 denotes a fluorine, chlorine, bromine or iodine atom, a C1.4-alkyl, trifluoromethyl or C^-alkoxy group or
two groups R13, if they are bound to adjacent carbon atoms, together denote a C3..5-alkylene, methylenedioxy or 1,3-bu- tadien-l,4-ylene group,
whilst of the abovementioned compounds the preferred ones are those wherein
Ra to Rd, A and X are as hereinbefore defined,
B denotes an R60-CO-alkylene-NR5, (R70-PO-OR8) -alkylene-NR5 or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by ah R60-CO or R60-CO-C1.2-alkyl group,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO-C1.4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C-^-alkyl group,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO- C1-4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C^-alkyl group,
a piperazino or homopiperazino group which in each case is substituted in the 4 position by an
Figure imgf000016_0001
bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-C0, (R70-PO-OR8) , (R70- PO-R9) ,
Figure imgf000017_0001
bis- (R60-CO) -C1.4-alkyl , (R70-PO-OR8) - C^-alkyl or (R70-PO-R9) -C^-alkyl group,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000017_0002
bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups ,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a C-^-alkyl, R60-CO-C1_4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group, whilst R6 to R9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups in each case are linked to a carbon atom of the group A, or
A and B together denote a hydrogen, fluorine or chlorine atom,
a C1-6-alkoxy group,
a C2.s-alkoxy group which is substituted from position 2 by a hydroxy, C1.4-alkoxy, amino, C1.4-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino or 4- (C1-4-alkyl) -homopiperazino group,
a Cj.g-alkoxy group which is substituted by an R60-CO, (R70-PO- OR8) or (R70-PO-R9) group,
a C4-7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group,
an amino, C^-alkylamino, di- (C1-4-alkyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino or 4-(C1.4-al- kyl) -homopiperazino group, a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
C denotes an
Figure imgf000018_0001
-0-C4.7-cycloalkylene, -0-C1.3-al- kylene-C3.7-cycloalkylene, -0-C4.7-cycloalkylene-C1-3-alkylene or -0-C1.3-alkylene-C3_7-cycloalkylene-C1_3-alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
an -O-Ci.g-alkylene group which is substituted by an R60-CO or
Figure imgf000018_0002
group, whilst R6 is as hereinbefore defined,
an -0-C2-6-alkylene group which is substituted from position 2 onwards by a hydroxy, C^-alkoxy, amino, C-^-alkylamino, di- (C.,_4-alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C^-alkyl) -piperazino group,
a -C^-alkylene group,
an -NR4-Cx.g-alkylene, -NR4-C3.7-cycloalkylene, -NR4-C1-3-alkylene- C3.7-cycloalkylene, -NR4-C3-7-cycloalkylene-C1.3-alkylene or -NR4-C1.3-alkylene-C3.7-cycloalkylene-Ci.3-alkylene group, whilst the -NR4- moiety of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
an oxygen atom, which is linked to a carbon atom of the group D, or
a NR4 group, this being linked to a carbon atom of the group D, and
D denotes an R60-CO-alkylene-NR5, (R7O-PO-0R8) -alkylene-NRs or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C1.2-alkyl groups or by an R60-CO or R60-CO-C1-2-alkyl group, a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, (R70-PO-OR8) , (R70-PO-R9) ,
Figure imgf000019_0001
bis- (RgO-CO) -C1.4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO- C^-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C1-4-alkyl group,
a piperazino or homopiperazino group which is substituted in each case in the 4 position by an R60-CO-C1.4-alkyl, bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) ,
Figure imgf000019_0002
, bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an RgO-CO-C1_4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups ,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a
Figure imgf000019_0003
(R7O-P0-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group, whilst R6 to R9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups are in each case linked to a carbon atom of the group C, or
C and D together denote a hydrogen, fluorine or chlorine atom,
a
Figure imgf000020_0001
group,
a C2.6-alkoxy group which is substituted from position 2 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino or 4- (C^-alkyl) -homopiperazino group,
a Ci.g-alkoxy group which is substituted by an R60-CO, (R70-PO- 0R8) or (R70-PO-R9) group,
a C4.7-cycloalkoxy or C3-7-cycloalkyl-C1.4-alkoxy group
an amino, C^-alkylamino, di- (C^-alkyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino or 4- (C^-alkyl) -homopiperazino group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups ,
with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R70-PO-OR8) or (R70-PO- R9) group, or
that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group, whilst in the abovementioned groups A to D R4 to R10 are as hereinbefore defined,
particularly those compounds wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms or
Rx together with R2, if they are bound to adjacent carbon atoms, denote a -CH=CH-CH=CH, -CH=CH-NH or -CH=N-NH group and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an -0-C1-4-alkylene , -0-C4.7-cycloalkylene , -O-C^-j-al- kylene-C3-7-cycloalkylene , -0-C4.7-cycloalkylene-C1.3-alkylene or -0-C1.3-alkylene-C3-7-cycloalkylene-C1.3-alkylene group , whilst the oxygen atom of the abovementioned groups in each 'case is linked to the bicyclic heteroaromatic ring,
an -0-C2_4-alkylene group which is substituted from position 2 onwards by a hydroxy group, whilst the oxygen atom of the abovementioned-0-C2.4-alkylene groups in each case is linked to the bicyclic heteroaromatic ring, or
an oxygen atom, this being linked to a carbon atom of the group B,
B denotes an R60-CO-alkylene-NR5, (R70-PO-OR8) -alkylene-NRs or (R70-PO-R9) -alkylene-NRs group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 4 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or
Figure imgf000022_0001
group, whilst
R5 denotes a hydrogen atom,
a C^-alkyl group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 by a hydroxy or C1-4-alkoxy group,
a C3.6-cycloalkyl or C3-6-cycloalkyl-C1.3-alkyl group,
R6, R7 and R8, which may be identical or different, in each case denote a hydrogen atom,
a C^-alkyl group which may be substituted from position 2 onwards by a hydroxy, C^-alkoxy or di- (C1-4-alkyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen atom or by an N- (C^-alkyl) -imino group, a C4.6-cycloalkyl group,
a C3.5-alkenyl or C3-5-alkynyl group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C3.g-cycloalkyl-C1.4-alkyl, aryl, aryl-C^,,-alky1 or RgCO-0- (ReCRf) group, whilst
Re and Rf, which may be identical or different, in each case denote a hydrogen atom or a C^-alkyl group and
Rg denotes a C^-alkyl, C3.6-cycloalkyl, C^-alkoxy or Cs.6-cycloalkoxy group,
and R9 denotes a C^-alkyl group,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, R60-CO-C1-4-alkyl or bis- (R60-C0) -C^-alkyl group wherein R6 is as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two RgO-CO or RgO-CO-C^-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, R60-CO-C1-4-alkyl or bis- (RεO-CO) - C^-alkyl group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two RgO-CO or RgO-CO-C1-4-alkyl groups wherein R6 and R10 are as hereinbefore defined, a piperazino or homopiperazino group which in each case is substituted in the 4 position by an R60-CO-C1-4-alkyl, bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an RgO-CO-C1-4-alkyl or bis- (R60-CO) -C^-alkyl group and is additionally substituted at cyclic carbon atoms by one or two R60-CO or
Figure imgf000024_0001
groups wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted in each case by an R60-CO,
Figure imgf000024_0002
or bis- (R60-C0) - C^-alkyl group wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or
Figure imgf000024_0003
groups wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-CO,
Figure imgf000024_0004
or bis- (RgO-CO) -C1-4-alkyl group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by two R60-CO or
Figure imgf000024_0005
groups wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C1-4-alkyl, bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000025_0001
or bis- (R60-CO) -C^-alkyl group, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by one or two R60-CO or
Figure imgf000025_0002
groups wherein R6 is as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 C^-alkyl groups,
a 2-oxo-morpholinyl group which is substituted. in the 4 position by a hydrogen atom, by a
Figure imgf000025_0003
group, whilst R6 is as hereinbefore defined and the above- mentioned 2-oxo-morpholinyl groups in each case are linked to a carbon atom of the group A,
an R1:LNR5 group wherein Rs is as hereinbefore defined and
Rxx denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydro- furan-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydro- pyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two methyl groups,
or A and B together denote a hydrogen atom,
a C1-4-alkoxy group,
a C2.4-alkoxy group which is substituted from position 2 by a hydroxy, C1-4-alkoxy, amino, C^-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C^-alkyl) -piperazino group,
a Cx.4-alkoxy group which is substituted by a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined, a C^-alkoxy group which is substituted by an R60-CO group, whilst R6 is as hereinbefore defined,
a C4.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group,
C denotes an -0-C1.4-alkylene, -0-C4-7-cycloalkylene, -O-Ci.3-alkylene-C3-7-cycloalkylene, -0-C4.7-cyclo- alkylene-C^-alkylene or -0-C1.3-alkylene-C3.7-cycloal- kylene-C1-3-alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
an -0-C2.4-alkylene group which is substituted from position 2 onwards by a hydroxy group, whilst the oxygen atom of the abovementioned-0-C2.4-alkylene groups in each case is linked to the bicyclic heteroaromatic ring, or
an oxygen atom, which is linked to a carbon atom of the group D,
D denotes an R60-CO-alkylene-NR5, (R70-PO-OR8) -alkylene-NRs or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 4 carbon atoms, may additionally be substituted by one or two C1.2-alkyl groups or by an R60-C0 or
Figure imgf000026_0001
group, whilst R5 to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, R60-CO-C1-4-alkyl or bis- (R60-CO) -C^-alkyl group wherein R6 is as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two RgO-CO or RgO-CO-C-^-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO,
Figure imgf000027_0001
or bis- (R60'-CO) - C^-alkyl group wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or
Figure imgf000027_0002
groups wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in each case in the 4 position by an
Figure imgf000027_0003
bis- (RgO-CO) -C1-4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an R60-CO-C1-4-alkyl or bis- (R60-CO) -C^-alkyl group and is additionally substituted at cyclic carbon atoms by one or two R60-CO or R60-CO-C1_4-alkyl groups wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted in each case by an R60-CO,
Figure imgf000027_0004
, or bis- (R60-CO) - C^-alkyl group wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or RgO-CO-C1.4-alkyl groups wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-CO,
Figure imgf000027_0005
or bis- (RgO-CO) -C^-alkyl group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the above- mentioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by two R60-CO or
Figure imgf000028_0001
groups wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000028_0002
bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000028_0003
or bis- (R60-CO) -Cx.4-alkyl group, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by one or two R60-CO or R60-CO-C1.4-alkyl groups wherein R6 is as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 C-^-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a
Figure imgf000028_0004
group, whilst R6 is as hereinbefore defined and the above- mentioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C,
an RnNR5 group wherein R5 and R x are as hereinbefore defined, or
C and D together denote a hydrogen atom,
a C^-alkoxy group,
a C2.4-alkoxy group which is substituted from position 2 by a hydroxy, C^-alkoxy, amino, C^-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C^-alkyl) -piperazino group, a C1-4-alkoxy group which is substituted by a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined,
a C1-4-alkoxy group which is substituted by an R60-CO group, whilst R6 is as hereinbefore defined,
a C4.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group
with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R70-PO-OR8) or (R70-PO- R9) group, or
that at least one of the groups B or D contains an optionally substituted 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran- 4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group, or
that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
whilst by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which in each case may be monosubstituted by R12, mono- or disubstituted by R13 or monosubstituted by R12 and additionally mono- or disubstituted by R13, whilst the substituents may be identical or different and
R12 denotes a cyano, C^-alkoxycarbonyl, aminocarbonyl , C^-alkylaminocarbonyl, di- (C^-alkyl) -aminocarbonyl, C1-2-alkylsulphenyl, C^-alkylsulphinyl, C^-alkylsulphonyl, hydroxy, nitro, amino, C1.4-alkylamino or di- (C^-alkyl) -amino group and
R13 denotes a fluorine, chlorine, bromine or iodine atom, a Ci.j-alkyl, trifluoromethyl or C1.2-alkoxy group or
two groups R13, if they are bound to adjacent carbon atoms, together denote a C -alkylene, methylenedioxy or 1,3-buta- dien-1, 4-ylene group,
the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of general formula I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an -0-C1-4-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, B denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst
R5 denotes a hydrogen atom,
a C1-2-alkyl group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 onwards by a hydroxy group,
a C3.6-cycloalkyl or C3.6-cycloalkylmethyl group and
Re denotes a hydrogen atom,
a Ci.g-alkyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCRf) group, whilst
Re denotes a hydrogen atom or a C^-alkyl group,
Rf denotes a hydrogen atom and
Rg denotes a C1.4-alkyl, cyclopentyl, cyclohexyl, C^-alkoxy, cyclopentyloxy or cyclohexyloxy group,
a pyrrolidino or piperidino group which is substituted by an RsO-CO or R60-CO-C1-2-alkyl group wherein R6 is as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by two RgO-CO or RgO-CO-C1-2-alkyl groups wherein R6 is as hereinbefore defined, a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or
Figure imgf000032_0001
group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RgO-CO-C^-alkyl, bis- (R60-CO) -C1-4-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 is as hereinbefore defined,
R7 and R8, which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCRf) group, whilst
Re to Rg are as hereinbefore defined,
and R9 denotes a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RgO-CO-Cj^-alkyl group and additionally at a cyclic carbon atom by an R60-CO or RgO-CO-C^j-alkyl group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or R60-CO- C1.2-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R60-CO-C1-4-alkyl , bis- (R60-CO) -C1-4-alkyl, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or RgO-CO-C1-2-alkyl group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups in each case are linked to a carbon atom of the group A, or
a R11N(C1.2-alkyl) group wherein Rxx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, or
A and B together denote a hydrogen atom, a methoxy, ethoxy or 2-methoxy-ethoxy group,
a Cl^-alkoxy group which is substituted by an R60-CO group, whil1st R6 is as hereinbefore defined,
a C4.6-cycloalkoxy or C3.6-cycloalkyl-C1.3-alkoxy group,
C denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
D denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst R5 and R6 are as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by an R60-CO or
Figure imgf000033_0001
group wherein R6 is as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by two RgO-CO or RgO-CO-C^-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or RgO-CO-C^-alkyl group wherein R6 and R10 are as hereinbefore defined, a piperazino group which is substituted in the 4 position by an
Figure imgf000034_0001
, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino group which is substituted in the 4 position by an
Figure imgf000034_0002
group and additionally at a cyclic carbon atom by an R60-CO or
Figure imgf000034_0003
group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or RεO-CO- C^-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an
Figure imgf000034_0004
, (R70-PO- OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups ,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or R60-CO-C1-2-alkyl group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C,
a R11N(C1.2-alkyl) group wherein RX1 denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, or
C and D together denote a hydrogen atom, a methoxy, ethoxy or 2-methoxy-ethoxy group,
a C^-alkoxy group which is substituted by an R60-CO group, whilst R6 is as hereinbefore defined,
a C4.g-cycloalkoxy or C3-6-cycloalkyl-C1.3-alkoxy group with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R70-PO-OR8) or (R70-PO- R9) group, or
that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of general formula I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
.a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom, A denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
B denotes an R60-CO-alkylene-NRs group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst
R5 denotes a hydrogen atom,
a C^-alky! group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 onwards by a hydroxy group,
a C3.6-cycloalkyl or C3.6-cycloalkylmethyl group and
R6 denotes a hydrogen atom,
a C-^g-alkyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCR£) group, whilst
Re denotes a hydrogen atom or a C^-alkyl group,
Rf denotes a hydrogen atom and
Rg denotes a C^-alkyl, cyclopentyl, cyclohexyl, C^-alkoxy, cyclopentyloxy or cyclohexyloxy group,
a pyrrolidino or piperidino group which is substituted by an RgO-CO or RgO-CO-C1-2-alkyl group wherein R6 is as hereinbefore defined, a pyrrolidino or piperidino group which is substituted by two RgO-CO or RgO-CO-Ci.j-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or
Figure imgf000037_0001
group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an
Figure imgf000037_0002
, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 is as hereinbefore defined,
R7 and R8, which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCRf) group, whilst
Re to Rg are as hereinbefore defined,
and R9 denotes a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an
Figure imgf000037_0003
group and is additionally substituted at a cyclic carbon atom by an R60-CO or
Figure imgf000037_0004
group wherein Rs is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or R60-CO- C1-2-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an RgO-CO-C^-alkyl, bis- (R60-CO) -C^-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined, a 2-oxo-morpholino group which may be substituted by '1 or 2 methyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or
Figure imgf000038_0001
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups in each case are linked to a carbon atom of the group A,
a R11N(C1.2-alkyl) group wherein RX1 denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, and
C and D together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C4.6-cycloalkoxy or C3.g-cycloalkyl-C1.3-alkoxy group,
particularly those compounds wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
R and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom, A and B together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C4.6-cycloalkoxy or C3.6-cycloalkyl-C1.3-alkoxy group,
C denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, and
D denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or RεO-CO- methyl group, whilst
Rs denotes a hydrogen atom,
a C^-alkyl group which may be substituted by an R60-CO group,
a C2-4-alkyl group which is substituted from position 2 by a hydroxy group,
a C3-g-cycloalkyl or C3.6-cycloalkylmethyl group and
R6 denotes a hydrogen atom,
a
Figure imgf000039_0001
cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 5-indanyl or RgC0-0- (ReCR£) group, whilst
Re denotes a hydrogen atom or a C1-4-alkyl group,
Rf denotes a hydrogen atom and
Rg denotes a C^-alkyl, cyclopentyl, cyclohexyl, C^-alkoxy, cyclopentyloxy or cyclohexyloxy group, a pyrrolidino or piperidino group which is substituted by an RgO-CO or
Figure imgf000040_0001
group wherein R6 is as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by two RgO-CO or
Figure imgf000040_0002
groups wherein R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or R60-CO-C1-2-alkyl group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RβO-CO-C1.4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 is as hereinbefore defined,
R7 and R8, which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCRf) group, whilst
Re to Rg are as hereinbefore defined,
and R9 denotes a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an
Figure imgf000040_0003
group and is additionally substituted at a cyclic carbon atom by an R60-CO or
Figure imgf000040_0004
group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or R60-CO- Cx.2-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an RgO-CO-C^-alkyl, bis- (R60-CO) -C^-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or
Figure imgf000041_0001
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C, or
a RιaN (C^-alkyl) group wherein Rxx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
the tautomers, stereoisomers and salts thereof.
The most preferred bicyclic heterocyclic compounds of general formula I, however, are those wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, B denotes an R60-CO-CH2-NR5 group wherein
R5 denotes a hydrogen atom or a methyl group which may be substituted by an R60-CO group, or
a C2.4-alkyl group substituted from position 2 onwards by a hydroxy group, and
R6 denotes a hydrogen atom, a methyl or ethyl group,
a pyrrolidino or piperidino group which is substituted by an RgO-CO group, whilst R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by an R60-CO-CH2 or bis- (R60-CO) -C1-3-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R60-CO-CH2 group, whilst R6 is as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by one or two methyl groups, or
a R11N(C1-2-alkyl) group wherein Rxx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, and
C and D together denote a methoxy, C4.s-cycloalkoxy or C3.6-cycloalkylmethoxy group,
particular those compounds wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A and B together denote a C4.6-cycloalkoxy or C3.6-cycloalkyl- methoxy group,
C denotes an -0-CH2CH2 group, whilst the oxygen atom of the abovementioned group is linked to the bicyclic heteroaromatic ring,
D denotes an R60-CO-CH2-NR5 group wherein
Rs denotes a C2.4-alkyl group substituted from position 2 onwards by a hydroxy group, and
R6 denotes a methyl or ethyl group,
a 2-oxo-morpholino group which may be substituted by one or two methyl groups , or
a R11N(C1.2-alkyl) group wherein Rxx denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group,
the tautomers, stereoisomers and salts thereof.
The following particularly preferred compounds of general formula I are mentioned by way of example:
(1) 4- (3-chloro-4-fluorophenylamino) -6- {3- [4- (methoxycarbonyl- methyl) -1-piperazinyl] propyloxy} -7-methoxy-quinazoline, (2) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] - piperazin-1-yl }ethoxy) -7-methoxy-quinazoline,
(3) ( S) -4- [ (3-bromophenyl) amino] -6- [3- (2-methoxycarbonyl- pyrrolidin-1-yl) propyloxy] -7-methoxy-quinazoline,
(4) 4- [ (3-bromophenyl) amino] -6- (3- {4- [ (ethoxycarbonyl) ethyl] - piperazin-1-yl} -2-hydroxy-propyloxy) -7-methoxy-quinazoline,
(5) ( S) -4- [ (3-bromophenyl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] -pyrrolidine-2-yl}methoxy) -7-methoxy-quinazoline and
(6) 4- [ (3-bromophenyl) amino] -6- (2- {4- [1,2 bis (methoxycarbonyl) ■ ethyl] -piperazin-1-yl} ethoxy) -7-methoxy-quinazoline
and the salts thereof.
The compounds of general formula I may, for example, be prepared by the following methods :
a) reacting a compound of general formula
Figure imgf000044_0001
wherein
Ra to Rd, C, D and X are as hereinbefore defined and
U denotes an oxygen atom or an R4N group, whilst R4 is as hereinbefore defined, with a compound of general formula
Zx - A1 - B (III) wherein
B is as hereinbefore defined,
A' denotes one of the optionally substituted alkylene, cycloal- kylene, alkylene-cycloalkylene, cycloalkylene-alkylene or alkylene-cycloalkylene-alkylene moieties mentioned above for the group A, which are linked to the heteroaromatic group via an oxygen atom or via an NR4 group, and
Z denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chloroben- zene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (Hϋnig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150 °C.
b) reacting a compound of general formula
Figure imgf000045_0001
wherein
Ra to Rd, A, B and X are as hereinbefore defined and denotes an oxygen atom or an R4N group, whilst R4 is as hereinbefore defined, with a compound of general formula Z2 - C - D , (V)
wherein
D is as hereinbefore defined,
C denotes one of the optionally substituted alkylene, cycloal- kylene, alkylene-cycloalkylene, cycloalkylene-alkylene or alkylene-cycloalkylene-alkylene moieties mentioned above for the group C, which are linked to the heteroaromatic group via an oxygen atom or via an NR4 group, and
Z2 denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chloroben- zene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (Hunig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of an alkali or alkaline earth metal alkoxide such as sodium ethoxide or potassium tert .butoxide conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
c) In order to prepare a compound of general formula I wherein A is as hereinbefore defined with the exception of the oxygen atom and the -NR4 group: reacting a compound of general formula
Figure imgf000047_0001
wherein
Ra to Rd, C, D and X are as hereinbefore defined and
A" has the meanings given for A hereinbefore with the exception of the oxygen atom and the -NR4 group and
Z3 denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group or together with a hydrogen atom of an adjacent hydrocarbon group denotes an oxygen atom, with a compound of general formula
H - B , (VII)
wherein
B is as hereinbefore defined.
The reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, ethanol, methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydro- furan or dioxane, optionally in the presence of a tertiary organic base such as triethylamine, pyridine or 2 -dimethyl- aminopyridine , in the presence of N-ethyl-diisopropylamine (Hύnig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of an alkali or alkaline earth metal alkoxide such as sodium ethoxide or potassium tert.but- oxide, conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150 °C. d) In order to prepare a compound of general formula I wherein C is as hereinbefore defined with the exception of the oxygen atom and the -NR4 group:
reacting a compound of general formula
, (Villi
Figure imgf000048_0001
wherein
C" has the meanings given for C hereinbefore with the exception of the oxygen atom and the -NR4 group and
Z4 denotes a leaving group such as a halogen atom or a sulpho- nyloxy group such as a chlorine or bromine atom, a methanesul- phonyloxy or p-toluenesulphonyloxy group or together with a hydrogen atom of an adjacent hydrocarbon group denotes an oxygen atom, with a compound of general formula
H - D (IX)
wherein
D is as hereinbefore defined.
The reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, ethanol, .methylene chloride, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydro- furan or dioxane optionally in the presence of a tertiary organic base such as triethylamine, pyridine or 2 -dimethyl- aminopyridine, in the presence of N-ethyl-diisopropylamine (Hύnig's base), whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of an alkali or alkaline 'earth metal alkoxide such as sodium ethoxide or potassium tert.but- oxide, conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
e) In order to prepare a compound of general formula I wherein B denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-C0 or
Figure imgf000049_0001
group, a piperazino or homopiperazino group substituted in the 4 position by an RgO-CO-C^-alkyl or bis- (R60-CO) -C1-4-alkyl group or a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an RεO-CO-C1-4-alkyl or bis- (R60-CO) -C^-alkyl group, whilst in each case R5 and Rε are as hereinbefore defined:
reacting a compound of general formula
Figure imgf000049_0002
wherein
Ra to Rd, A, C, D and X are as hereinbefore defined and
B' denotes an R5NH group wherein R5 is as hereinbefore defined, a piperazino or homopiperazino group unsubstituted in the 4 position, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group unsubstituted in the 1 position, with a compound of general formula
R60-CO-alkylene-Z5 , (XI) wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C1-2-alkyl groups or by an R60-CO or
Figure imgf000050_0001
group, whilst R6 in each case is as hereinbefore defined, and Z5 denotes an exchangeable group such as a halogen atom or a substituted sulphonyloxy group, e.g. a chlorine or bromine atom, a methylsulphonyloxy, propylsulphonyloxy, phenylsulphonyloxy or benzylsulphonyloxy group.
The reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethyl- formamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hύnig's base) , whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
f) In order to prepare a compound of general formula I wherein D denotes an R60-CO-alkylene-NRs group wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C1-2-alkyl groups or by an R60-C0 or
Figure imgf000050_0002
group, a piperazino or homopiperazino group substituted in the 4 position by an RgO-CO-C^-alkyl or bis- (R60-CO) -C^-alkyl group or a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000050_0003
or bis- (RεO-CO) -C1-4-alkyl group, whilst in each case R5 and R6 are as hereinbefore defined: reacting a compound of general formula
Figure imgf000051_0001
wherein
Ra to Rd, A to C and X are as hereinbefore defined and
D' denotes an R5NH group wherein R5 is as hereinbefore defined, a piperazino or homopiperazino group unsubstituted in the 4 position, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group unsubstituted in the 1 position, with a compound of general formula
R60-CO-alkylene-Z5 (XI)
wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two
Figure imgf000051_0002
group, whilst R6 in each case is. as hereinbefore defined, and
Z5 denotes an exchangeable group such as a halogen atom or a substituted sulphonyloxy group, e.g. a chlorine or bromine atom, a methylsulphonyloxy, propylsulphonyloxy, phenylsulpho- nyloxy or benzylsulphonyloxy group.
The reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethyl- formamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hύnig's base) , whilst these organic bases may simultaneously serve as solvents, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution conveniently at temperatures between -20 and 200°C, preferably at temperatures between 0 and 150°C.
g) In order to prepare a compound of general formula I wherein at least one of the groups R6 to R8 denotes a hydrogen atom:
Converting a compound of general formula
Figure imgf000052_0001
wherein
Ra to Rd, A, C and X are as hereinbefore defined,
B" and D" have the meanings given for B and D hereinbefore, with the proviso that at least one of the groups B" or D" contains an R60-CO, (R70-PO-OR8) or (R70-PO-R9) group wherein R9 is as hereinbefore defined and at least one of the groups R6 to
R8 does not represent a hydrogen atom, by hydrolysis, treating with acids, thermolysis or hydrogenolysis, into a compound of general formula I wherein at least one of the groups Rs to R8 denotes a hydrogen atom.
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoro- acetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol , water/ethanol, water/isopropanol , methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 120°C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. If B" or D" in a compound of formula X for example contains the tert .butyloxycarbonyl group, the tert.butyl group may also be cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120°C, e.g. at temperatures between 0 and 60°C, or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120°C. Under the reaction conditions mentioned above, any N-tert .butyloxycarbonylamino or N-tert .butyloxycarbonylimino groups present may be converted into the corresponding amino or imino groups .
If B" or D" in a compound of formula X for example contains the benzyloxycarbonyl group, the benzyl group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. ambient temperature, and at a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis other groups may simultaneously be converted, e.g. a nitro group may be converted into an amino group, a benzyloxy group into a hydroxy group and a N-benzylamino, N-benzylimino, N-benzyloxycarbonyl- amino or N-benzyloxycarbonylimino group into a corresponding amino or imino group .
If according to the invention a compound of general formula I is obtained which contains a carboxy or hydroxyphosphoryl - 52 -
group, this may be converted by esterification into a corresponding ester of general formula I or
If a compound of general formula I is obtained wherein B or D denotes an optionally substituted N- (2-hydroxyethyl) -glycine or N- (2-hydroxyethyl) -glycinester group, this may be converted by cyclisation in a corresponding 2-oxo-morpholino compound.
The subsequent esterification is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or particularly advantageously in a corresponding alcohol, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N' -dicyclo- hexylcarbodiimide, N,N' -dicyclohexylcarbodiimide/N-hydroxy- succinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N,N' -carbonyldiimidazole or triphenyl-phosphine/carbon tetrachloride, conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 80°C.
The subsequent ester formation may also be carried out by reacting a compound which contains a carboxy or hydroxy- phosphoryl group with a corresponding alkyl halide.
The subsequent intramolecular cyclisation is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, tetrahydrofuran, dioxane or toluene in the presence an acid such as hydrochloric acid or p-toluenesulphonic acid at temperatures between -10 and 120°C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, phosphono, O-alkyl-phosphono, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,-
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group,
protecting groups for a phosphono group may be an alkyl group such as the methyl, ethyl, isopropyl or n-butyl group, the phenyl or benzyl group, and
protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.but- oxycarbonyl, benzyloxycarbonyl, benzyl , methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group .
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroace- tic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120°C, preferably at temperatures between 10 and 100°C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100°C, but preferably at temperatures between 20 and 60°C, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2, 4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert .butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120°C or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50°C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, iso- propanol, toluene/water or dioxane at temperatures between 20 and 50°C.
A single alkyl group may be cleaved from an 0,0' -dialkylphos- phono group with sodium iodide, for example, in a solvent such as acetone, methylethylketone, acetonitrile or dimethylform- amide at temperatures between 40 and 150°C, but preferably at temperatures between 60 and 100°C.
Both alkyl groups may be cleaved from an 0,0' -dialkyl-phos- phono group with iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane/sodium iodide, for example, in a solvent such as methylene chloride, chloroform or acetonitrile at temperatures between 0°C and the boiling temperature of the reaction mixture, but preferably at temperatures between 20 and 60°C. Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as race- mates may be separated by methods known per se (cf . Allinger
N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, ma.lic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example {+) or (-) -menthol and an optically active acyl group in amides, for example, may be a (+)-or ( - ) -menthyloxycarbonyl .
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy, hydroxyphosphoryl , sulpho or 5-tetrazolyl group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof . Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexyl- amine, ethanolamine, diethanolamine and triethanolamine .
The compounds of general formulae II to XIII used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf . Examples I to XVI) .
As already mentioned hereinbefore, the compounds of general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R) , whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible to block the transmission of signals to components located further down.
The biological properties of the new compounds were investigated as follows: The inhibition of the EGF-R-mediated signal transmission can be demonstrated e.g. with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. A cell line of murine origin dependent on interleukin-3- (IL-3) which was genetically modified to express functional human EGF-R was used here. The proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf . von Rϋden, T. et al . in EMBO J. 2, 2749-2756 (1988) and Pierce, J. H. et al . in Science 2.19., 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell line FDC-Pi, the production of which has been described by Dexter, T. M. et al . in J. Exp. Med. 152 r 1036-1047 (1980). Alternatively, however, other growth-factor-dependent cells may also be used (cf. for example Pierce, J. H. et al . in Science 223., 628-631 (1988), Shibuya, H. et al . in Cell _7_Q, 57-67 (1992) and Alexander, W. S. et al . in EMBO J. ID., 3683- 3691 (1991)). For expressing the human EGF-R cDNA (cf. Ullrich, A. et al . in Nature 3UU, 418-425 (1984)) recombinant retroviruses were used as described by von Rύden, T. et al . , EMBO J. 2, 2749-2756 (1988) , except that the retroviral vector LXSN (cf. Miller, A. D. et al . in BioTechniques 1, 980-990 (1989)) was used for the expression of the EGF-R cDNA and the line GP+E86 (cf. Markowitz, D. et al. in J. Virol. £L2., 1120- 1124 (1988)) was used as the packaging cell.
The test was performed as follows :
F/L-HERc cells were cultivated in RPMl/1640 medium (BioWhittaker) , supplemented with 10 % foetal calf serum (FCS, Boehringer Mannheim) , 2 mM glutamine (BioWhittaker) , standard antibiotics and 20 ng/ml of human EGF (Promega) , at 37°C and 5% CO2. In order to investigate the inhibitory activity of the compounds according to the invention, 1.5 x 104 cells per well were cultivated in triplicate in 96-well dishes in the above medium (200 μl) , the cell proliferation being stimulated with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. Karasuyama, H. et al . in Eur. J. Immunol. IR, 97-104 (1988) ) . The compounds according to the invention were dissolved in 100% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37°C.
In order to determine the inhibitory activity of the compounds according to the invention the relative cell number was measured in O.D. units using the Cell Titer 96™ AQueθus Non- Radioactive Cell Proliferation Assay (Promega) . The relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was derived therefrom. The following results were obtained:
Figure imgf000060_0001
The compounds of general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosinekinases . These are e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoan- giogenesis) .
The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosinekinases', e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiecta- sias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, αl-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosinekinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn" s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Menetrier's disease, secreting adenomas and protein loss syndrome, and also for treating nasal polyps and polyps of the gastrointestinal tract of various origins such as e.g. villous or adenomatous polyps of the large bowel, but also polyps in familial polyposis coli, intestinal polyps in Gardner's syndrome, polyps throughout the entire gastrointestinal tract in Peutz-Jeghers syndrome, in inflammatory pseudopolyps, juvenile polyps, Colitis cystica profunda and Pneumatosis cystoides intestinales .
Moreover, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly in cystic changes such as cystic kid- neys, for treating renal cysts which may be idiopathic in origin or occur in syndromes such as e.g. tuberculous sclerosis, in von-Hippel-Lindau Syndrome, in nephronophthisis and spongy kidney and other diseases caused by aberrant function of tyrosinekinases, such as e.g. epidermal hyperproliferation (psoriasis) , inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, etc.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide) , mitosis inhibitors (e.g. vinblastin) , compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adria- mycin) , hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti- inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion or antiinflammatory substances. These combinations may be administered either simultaneously or sequentially.
These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intrarectal, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation. For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
The following Examples are intended to illustrate the present invention without restricting it:
Preparation of the starting compounds:
Kxampl T
4- (3-chloro-4-fluorophenylamino) -6- [3- (4 -tert . butyloxycarbonyl- p-i era7:-iτιo) -propyloxy] -7-methoxy-qιn na oline
500 mg of 4- (3-chloro-4-fluorophenylamino) -6 -hydroxy- 7-methoxy- quinazoline, 600 mg of 1- [3- (methanesulphonyloxy) propyl] - 4 -tert . butyloxycarbonyl-piperazine (prepared by reacting 1- (3-hydroxypropyl) -4 -tert .butyloxycarbonyl-piperazine with methanesulphonic acid anhydride in the presence of triethylamine) and 520 mg of potassium carbonate are stirred in 20 ml of dimethylformamide for 8 hours at 80 °C. A further 300 mg of the piperazino compound are added and stirring is continued for another 4 hours at 80 °C. The reaction mixture is concentrated by evaporation and the residue is divided between water and ethyl acetate. The organic phase is concentrated by evaporation and the residue is purified by chromatography on a silica gel column with ethyl acetate. Yield: 700 mg of (82 % of theory) ,
Rf value: 0.29 (silica gel; ethyl acetate/methanol = 9:1) Mass spectrum: (M-H) = 544, 546
The following compounds are obtained analogously to Example I :
(1) 4- (3-chloro-4-fluorophenylamino) -6- [3- (1-tert .butyloxycarbonyl -4 -piperidinyl) -propyloxy] -7-methoxy-quinazoline
Rf value: 0.70 (silica gel; ethyl acetate/methanol = 9:1)
(2) ( S) -4- [ (3-bromophenyl) amino] -6-{ [1- (tert .butyloxycarbonyl) - pyrrolidine-2 -yl] methoxy} -7-methoxy-quinazoline melting point: 178°C
Mass spectrum (ESI"): m/z = 527, 529 [M-H] "
(3) (R) -4- [ (3-bromophenyl) amino] -6- { [1- (tert .butyloxycarbonyl) - pyrrolidine-2-yl] methoxy} -7-methoxy-quinazoline
Rf value: 0.65 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (El) : m/z = 528, 530 [M] +
(4) ( S) -4- [ (3-chloro-4-fluoro-phenyl) amino] -6- { [1- (tert .butyloxycarbonyl) -pyrrolidin-2-yl] methoxy} -7-cyclopentyloxy-quina- zoline
Rf value: 0.76 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 555, 557 [M-H]"
(5) ( S) -4- [ (3-chloro-4-fluoro-phenyl) amino] -6- { [1- (tert .butyloxycarbonyl) -pyrrolidin-2-yl] methoxy} -7-cyclopentylmethoxy- quinazoline
Melting point: 210-211.5°C
Mass spectrum (ESI"): m/z = 569, 571 [M-H]"
Rxampl e TT
4- (3-chloro-4-fluorophenylamino) -6- [3- (1-piperazinyl) -propyl - oxyl -7-τne hoxy-qn-iπa7.o1 ine
600 mg of 4- (3-chloro-4-fluorophenylamino) -6- [3- (4-tert . butyl - oxycarbonylpiperazino) propyloxy] -7-methoxy-quinazoline in 5 ml methylene chloride are mixed with 1.5 ml of trifluoroacetic acid and stirred for 2 hours at ambient temperature. The reaction mixture is concentrated by evaporation and combined with 2N NaOH. It is decanted off the sticky residue, the residue is taken up in methanol, concentrated by evaporation and triturated with diethyl ether. Yield: 280 mg of (50 % of theory),
Rt value: 0.49 (aluminium oxide; ethyl acetate/methanol/conc . aqueous ammonia = 9:1:0.1)
Mass spectrum: (M+H) + = 446, 448
The following compounds are obtained analogously to Example II
(1) 4- (3~chloro-4-fluorophenylamino) -6- [3- (4 -piperidinyl) propyloxy] -7-methoxy-quinazoline R£ value: 0.33 (aluminium oxide; ethyl acetate/methanol/conc . aqueous ammonia = 9:1:0.1)
Mass spectrum: (M+H) + = 445, 447
(2) ( S) -4- [ (3-bromophenyl) amino] -6- [ (pyrrolidine-2-yl) methoxy] -
7-methoxy-quinazoline melting point: 143 °C
Mass spectrum (ESI+) : m/z = 429, 431 [M+H] +
(3) (R) -4- [ (3-bromophenyl) amino] -6- [ (pyrrolidine-2 -yl) methoxy] -
7-methoxy-quinazoline
Rf value: 0.21 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution = 9:1:0.1)
(4) ( S) -4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [ (pyrrolidin-
2 -yl) methoxy] -7-cyclopentyloxy-quinazoline
Rf value: 0.18 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI") : m/z = 455, 457 [M-H]"
(5) ( S) -4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [ (pyrrolidin-
2-yl) methoxy] -7-cyclopentylmethoxy-quinazoline
Rf value: 0.36 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI+) : m/z = 471, 473 [M+H] +
Example III
N- (3-Brompropyl) sarcosine ethyl ester and N- (3-chloropropyl) - sarmsinp ethyl ester
6.9 ml of 1, 3-dibromopropene in 20 ml acetonitrile are added dropwise to 2.4 g of sarcosine ethyl ester hydrochloride and 6 ml of N-ethyl-diisopropylamine in 50 ml of acetonitrile. After stirring overnight at ambient temperature the mixture is concentrated by evaporation and the residue is divided between ethyl acetate and water. The organic phase is concentrated by evaporation and the residue is purified by chromatography on silica gel (ethyl acetate/methanol = 9:1).
Yield: 0.77 g,
R£ value: 0.80 (silica gel; ethyl acetate/methanol = 9:1)
Mass spectrum: M+ = 237, 239 and 193, 195
The following compounds are obtained analogously to Example III:
(1) ( S) -N- (3 -Bromopropyl) proline methyl ester and
( S) -N- (3-chloropropyl) proline methyl ester
Rf value: 0.84 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (El): m/z = 249, 251 [M] + and 205, 207 [M] +
(2) (R) '-N- (3 -bromopropyl) proline methyl ester and
(R) -N- (3 -chloropropyl) proline methyl ester
Rf value: 0.84 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (El): m/z = 249, 251 [M] + and 205, 207 [M] +
Examp] e IV
4- r (3-bromophenyl ) aminol -6- (2-bromethoxy) -7-methoyy-qιιi na^nl.i ne
7.00 g of potassium carbonate and 8.70 ml of dibromoethane are added to 3.50 g of 4- [ (3-bromophenyl) amino] -6-hydroxy-7- methoxy-quinazoline in 350 ml dimethylformamide . The reaction mixture is stirred for two hours at 85°C. Then the mixture is concentrated by evaporation and the oily residue is stirred with methanol. The bright yellow precipitate formed is suction filtered and dried.
Yield: 3.70 g (81 % of theory),
Rf value: 0.44 (silica gel, ethyl acetate)
Mass spectrum (ESI+) : m/z = 452, 454, 456 [M+H] +
The following compounds are obtained analogously to Example IV: (1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- (2-bromo-ethoxy) - 7-cyclopentyloxy-quinazoline
Rf value: 0.74 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:1)
Mass spectrum (ESI"): m/z = 478, 480, 482 [M-H]"
(2) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy- 7- (2-bromo-ethoxy) -quinazoline
Rf value: 0.65 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 478, 480, 482 [M-H]"
Fxampl e V
4- r (3-hrnmophenyl ) aminol -6-hydroxy-7-methoxy-q^ina7,o1 ins 34.50 g of 4- [ (3-bromophenyl) amino] -6-methylcarbonyloxy- 7-methoxy-quinazoline in 350 ml ethanol are mixed with 35 ml of 40% sodium hydroxide solution. The reaction mixture is stirred for three hours at ambient temperature . Then the mixture is concentrated by evaporation, the residue is taken up in water and neutralised with 2N hydrochloric acid. The precipitate formed is suction filtered and dried overnight in the circulating air drier at 50°C. Yield: 28.30 g (92 % of theory), melting point: 299°C Mass spectrum (ESI+) : m/z = 346, 348 [M+H] +
The following compounds are obtained analogously to Example V:
(1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7-hydroxy- quinazoline (The reaction is carried out with concentrated aqueous ammonia in methanol . )
Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1) Mass spectrum (ESI+) : m/z = 396, 398 [M+H] + (2) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-
7-hydroxy-quinazoline (The reaction is carried out with concentrated aqueous ammonia in methanol . )
R£ value: 0.53 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI+) : m/z = 374, 376 [M+H] +
Fxampl VI
4- [ (3-bromophenyl) amino] -6-methylcarbonyloxy-7-methoxy- qninay.ol i TIP
13.0 ml of 3-bromoaniline are added to 30.00 g of 4-chloro-
6-methylcarbonyloxy-7-methoxy-quinazoline in 600 ml isopro- panol . The reaction mixture is refluxed for about four hours.
The reaction mixture is then left to cool . The precipitate formed is suction filtered, washed thoroughly with cold iso- propanol and dried.
Yield: 34.57 g (75 % of theory), melting point: 238°C
Mass spectrum (ESI+) : m/z = 388, 390 [M+H] +
The following compounds are obtained analogously to Example VI
(1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7-me- thylcarbonyloxy-quinazoline
Melting point: 267-268 °C
Mass spectrum (ESI+) : m/z = 438, 440 [M+H] +
(2) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy- 7-methylcarbonyloxy-quinazoline
Rf value: 0.73 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI+) : m/z = 416, 418 [M+H] + Example VII
4- [ (3-bromophenyl) amino] -6-oxiranylmethoxy-7-methoxy- iinazoline
1.50 ml of epibromohydrin are added to 5.00 g of
4- [ (3-bromophenyl) amino] -6-hydroxy-7-methoxy-quinazoline and
4.75 g of potassium carbonate in 50 ml dimethylsulphoxide . The reaction mixture is stirred for two days at 50°C. Then it is diluted with about 150 ml of water and stirred for a further two hours. The precipitate formed is suction filtered and purified by chromatography on a silica gel column with ethyl acetate as eluant .
Yield: 850 mg (15 % of theory), melting point: 230-245°C
Mass spectrum (ESI+) : m/z = 402, 404 [M+H] +
Example VTII
Dimethyl 2- (pi perazi n-1 -yl ) -πucc nate rii hyri-ro hl ori p
8.70 g of dimethyl 2- (4-benzyl-piperazin-l-yl) -succinate are hydrogenated in a mixture of 100 ml methanol and 4.50 ml of concentrated hydrochloric acid in the presence of 4.00 g of palladium (10% on activated charcoal) at ambient temperature until the calculated amount of hydrogen is taken up (about an hour) . Then the catalyst is removed by suction filtering and the filtrate is concentrated by evaporation. A white gel-like solid is left.
Yield: 4.18 g
Rf value: 0.80 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 1:1:1)
Mass spectrum (ESI+) : m/z = 231 [M+H] +
The following compound is obtained analogously to Example VIII:
(1) dimethyl 3- (piperazin-1-yl) -glutarate dihydrochloride Rf value: 0.80 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 1:1:1) Mass spectrum (ESI+) : m/z = 254 [M+H] +
Fxampl e TX
Di ethyl 2- (4-ben7.yl -piperazin-l -yl ) -πn c-i na e
7.22 ml of dimethyl maleate are added to 10.0 ml of N-benzyl- piperazine in 15 ml dioxane. The reaction mixture is stirred for half an hour at ambient temperature. Then the mixture is refluxed for about a further three hours. For working up the reaction mixture is evaporated to dryness. An orange-yellow oil remains, which slowly crystallises.
Yield: 21.3 g (crude product),
Rf value: 0.85 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution =
90:10:0.5)
Mass spectrum (El): m/z = 320 [M] +
The following compound is obtained analogously to Example IX:
(1) dimethyl 3- (4-benzyl-piperazin-l-yl) -glutarate (reaction with dimethyl glutaconate)
Rf value: 0.49 (silica gel, eyelohexane/ethyl acetate = 1:1) Mass spectrum (El) : m/z = 334 [M] +
Example X
4- [ (3 -Chloro-4-fluoro-phenyl) amino] -6-hydroxy-7-cyclopentyl- oxy-quinazol ne
10 ml of trifluoroacetic acid are added to 1.95 g of 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7-cyclo- pentyloxy-quinazoline and the resulting dark brown solution is stirred at room temperature over night. Another 5 ml of tri- fluoroacetic acid are added and the mixture is stirred for approximately 2.5 hours at 50°C until the reaction is completed. The reaction mixture is concentrated in vacuo, diluted with water, and adjustet to pH 8-9 by addition of concentrated aqueous ammonia. The precipitate is filtered off with suction, washed with water, and dried in vacuo at 60°C.
Yield: 1.45 g (92 % of theory),
Rf value: 0.56 (silica gel, methylene chloride/methanol 9:1)
Mass spectrum (ESI"): m/z = 372, 374 [M-H]"
The following compound is obtained analogously to Example X:
(1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-hydroxy-7-cyclo- pentylmethoxy-quinazoline
Rf value: 0.73 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1) Mass spectrum (ESI"): m/z = 386, 388 [M-H]"
Example XI
4- [ (3-chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7-cyclopentyl oxy-qui.nazoline
0.65 ml of bromocyclopentane are added to a mixture of 2.30 g 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7-hydroxy- quinazoline and 6.00 g potassium carbonate in 6 ml of N,N-di- methyl-formamide and the reaction mixture is stirred for 18 hours at room temperature. Another 3.00 g of potassium carbonate and 4 drops of bromocyclopentane are added, and the resulting mixture is stirred for 2.5 hours at 50°C. The reaction mixture is partitioned between ethyl acetate and water, and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with concentrated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo . The oily residue is triturated with methanol, the resulting solid precipitate is filtered off, washed with cold methanol, and dried in vacuo .
Yield: 2.09 g (77 % of theory),
Rf value: 0.63 (silica gel, methylene chloride/methanol 9:1)
Mass spectrum (ESI"): m/z = 462, 464 [M-H]"
The following compound is obtained analogouslyto Example XI : (1) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-benzyloxy-7-cyclo- pentylmethoxy-quinazoline
Rf value: 0.84 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10: 1) Mass spectrum (ESI+) : m/z = 478, 480 [M+H] +
Example XII
4-chlorn-6-benzyloxy-7-methylcarbonyloxy-qiiina7.nl inp Prepared by reaction of 6-benzyloxy-7-methylcarbonyloxy-3H- quinazolin-4-one with thionyl chloride in the presence of catalytic amounts of N,N-dimethyl-formamide.
Yield: 98 % of theory,
Rf value: 0.86 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
The following compound is obtained analogously to Example XII:
(1) 4-chloro-6-cyclopentyloxy-7-methylcarbonyloxy-quinazoline Rf value: 0.69 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Example XIII
6-benzylnxy-7-methylcarbonyloxy-3H-quinazol.in-4-one
Prepared by reaction of 6-benzyloxy-7-hydroxy-3H-quinazolin-
4-one with acetic anhydride in pyridine.
Yield: 68 % of theory,
Melting point: 231-233°C
Mass spectrum (ESI"): m/z = 309 [M-H]"
The following compound is obtained analogously to Example XIII:
(1) 6-cyclopentyloxy-7-methylcarbonyloxy-3H-quinazolin-4 -one Rf value: 0.57 (silica gel, methylene chloride/methanbl/concen- trated aqueous ammonia = 90:10:0.1) Mass spectrum (ESI"): m/z = 287 [M-H]"
Example XIV
6-Beng:yloxy-7-hydroxy-3H-quinazolin-4-one
Prepared by reaction of 2-amino-4-hydroxy-5-benzyloxy-benzoic acid with formamidine acetate in ethanol .
Yield: 72 % of theory,
Rf value: 0.45 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 267 [M-H]"
The following compound is obtained analogously to Example XIV:
(1) 6-cyclopentyloxy-7-hydroxy-3H-quinazolin-4-one
Rf value: 0.42 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1) Mass spectrum (El) : m/z = 246 [M] +
Example XV
2-Amino-4-hydroxy-5-benzyloxy-benzoic acid
Prepared by catalytic hydrogenation of 2-nitro-4-hydroxy-
5-benzyloxy-benzoic acid with Raney nickel in methanol.
Yield: 71 % of theory,
Rf value: 0.53 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 258 [M-H]"
The following compound is obtained analogously to Example XV:
(1) 2-amino-4-hydroxy-5-cyclopentyloxy-benzoic acid Rf value: 0.38 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia = 90:10:0.1) Mass spectrum (ESI"): m/z = 236 [M-H]" Exampl e XVT
?-Ni trn- -hydroxy- 5 -benzyl oxy-benzoi r. ariH
4.8 g of sodium are added portionwise to a mixture of 20.30 g 6-nitro-benzo [1, 3] dioxole-5-carboxylic acid and 81.2 ml of benzyl alcohol in 120 ml of dimethyl sulfoxide cooled in an ice/water bath. The reaction mixture is allowed to warm up to room temperature and stirred for approximately 21 hours. The brownish red solution is diluted with 600 ml of water and extracted with methylene chloride. The aqueous layer is acidified with concentrated hydrochloric acid and stirred for two hours at room temperature. The precipitate is filtered off, washed with water, and dried. Yield: 18.63g (67 % of theory), Melting point: 172-175°C Mass spectrum (ESI"): m/z = 288 [M-H]"
The following compound is obtained analogously to Example XVI :
(1) 2-nitro-4-hydroxy-5-cyclopentyloxy-benzoic acid Rf value: 0.61 (silica gel, toluene/l, 4-dioxane/ethanol/acetic acid = 90:10:10:6) Mass spectrum (ESI"): m/z = 266 [M-H]"
Preparation of the end products:
Example 1
4- (3-chloro-4-fluorophenylamino) -6- {3- [4- (methoxycarbonylme- hyl ) - 1 -pi erazinyl 1 ropyloxy} -7-methoxy-quinazoline
0.07 ml of methyl bromoacetate in 1 ml of acetonitrile is added dropwise to 250 mg of 4- (3-chloro-4-fluorophenylamino) -6- [3- (1- piperazinyl) propyloxy] -7-methoxy-quinazoline and 0.13 ml N- ethyl-diisopropylamine in 5 ml of acetonitrile. After 2 hours' stirring at ambient temperature the mixture is concentrated by evaporation, mixed with water and extracted with ethyl acetate. The organic phases are washed with saline solution, then dried with magnesium sulphate and concentrated by evaporation. Yield: 150 mg (51 % of theory),
Rf value: 0.54 (silica gel; ethyl acetate/methanol/conc . aqueous ammonia = 9:1:0.1) Mass spectrum: (M-H) = 516, 518
The following compounds are obtained analogously to Example 1 :
(1) 4- (3-chloro-4-fluorophenylamino) -6- {3- [1- (methoxycarbonyl- methyl) - -piperidinyl] propyloxy} -7-methoxy-quinazoline
R£ value: 0.79 (silica gel; ethyl acetate/methanol/conc. aqueous ammonia = 9:1:0.1)
Mass spectrum: M+ = 516, 518
(2) ( S) -4- [ (3-bromophenyl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] -pyrrolidin-2-yl}methoxy) -7-methoxy-quinazoline
Rf value: 0.68 (silica gel, ethyl acetate/methanol/concentrated aqueous ammonia solution = 9:1:0.1) Mass spectrum (El): m/z = 514, 516 [M] +
(3) (R) -4- [ (3-bromophenyl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] -pyrrolidin-2-yl}methoxy) -7-methoxy-quinazoline
R£ value: 0.75 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (El) : m/z = 514, 516 [M] + (4) (5) -4- [ (3-chloro-4-fluoro-phenyl) amino] -6- ( {l- (methoxycarbonyl) methyl] -pyrrolidin-2-yl}methoxy) -7-cyclopentyloxy- quinazoline
Rf value: 0.59 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 527, 529 [M-H]"
(5) ( S) -4- [ (3-chloro-4-fluoro-phenyl) amino] -6- ( {l- (methoxycarbonyl) methyl] -pyrrolidin-2-yl}methoxy) -7-cyclopentyl- methoxy-quinazoline
Rf value: 0.67 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 541, 543 [M-H]"
Example 2
4- (3 -chloro-4-fluorophenylamino) -6- {3- [N- (ethoxycarbonylme- hyl ) -N-methylaminol propyloxy} -7-methoxy-quinazoline
380 mg of a mixture of N- (3-bromopropyl) sarcosine ethyl ester and N- (3 -chloropropyl) sarcosine ethyl ester in 5 ml dimethyl- formamide are added dropwise to 500 mg of 4- (3-chloro-4-fluorophenylamino) -6-hydroxy-7-methoxy-quinazoline and 220 mg of potassium tert .butoxide in 15 ml dimethylformamide. After 3 hours' stirring at 80°C and standing overnight a further 110 mg of potassium tert .butoxide and 190 mg of the sarcosine mixture are added and the reaction mixture is stirred for 4 hours at 80°C. It is filtered, the filtrate is concentrated by evaporation, the residue is .taken up in water and extracted with ethyl acetate. The organic phase is separated off, dried and concentrated by evaporation. The residue is purified by chromatography on a silica gel column. Yield: 390 mg of (52 % of theory),
Rf value: 0.68 (silica gel; ethyl acetate/methanol/conc. aqueous ammonia = 9:1:0.1) Mass spectrum: (M-H) = 475, 477 The following compounds are obtained analogously to Example 2 :
(1) ( S) -4- [ (3-bromophenyl) amino] -6- [3- (2 -methoxycarbonyl- pyrrolidin-1-yl) propyloxy] -7-methoxy-quinazoline
R£ value: 0.38 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (El): m/z = 514, 516 [M] +
(2) (R) -4- [ (3-bromophenyl) amino] -6- [3- (2-methoxycarbonyl- pyrrolidin-1-yl) propyloxy] -7-methoxy-quinazoline
R£ value: 0.41 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (El) : m/z = 514, 516 [M] +
Exampl e 3
4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] - p perazin-1 -yl.} ethoxy) -7-methoxy-quinazoline
1.50 ml of diisopropyl-ethylamine and 1.10 ml of 1- [ (ethoxycarbonyl) methyl] -piperazine are added to 1.00 g of 4- [(3-bromophenyl) amino] -6- (2-bromoethoxy) -7-methoxy-quinazoline in 20 ml acetonitrile. The reaction mixture is stirred for two days at ambient temperature. The precipitate formed is filtered off and the filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate and washed once with saturated sodium hydrogen carbonate solution and once with water. The organic phase is dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on a silica gel column with ethyl acetate/ethanol/concentrated aqueous ammonia solution (9:1:0.1) as eluant . Yield: 450 mg of (38 % of theory) , melting point: 155°C Mass spectrum (El): m/z = 543, 545 [M] +
The following compounds are obtained analogously to Example 3 :
(1) 4- [ (3-bromophenyl) amino] -6- (2-{N- [ (ethoxycarbonyl) methyl] - N-methylamino}ethoxy) -7-methoxy-quinazoline R£ value: 0.55 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (El): m/z = 488, 490 [M] +
(2) 4- [ (3-bromophenyl) amino] -6- (2-{N,N-bis [ (ethoxycarbonyl) methyl] amino} ethoxy) -7-methoxy-quinazoline
R£ value: 0.38 (silica gel, ethyl acetate) Mass spectrum (El): m/z = 560, 562 [M] +
(3) 4- [ (3-bromophenyl) amino] -6- (2- {4- [1,2 bis (methoxycarbonyl) ethyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
R£ value: 0.61 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (El): m/z = 601, 603 [M] +
(4) 4- [ (3-bromophenyl) amino] -6- [2- (4-{l- [ (methoxycarbonyl) methyl] -2- (methoxycarbonyl) -ethyl} -piperazin-1-yl) ethoxy] -
7 -methoxy-quinazoline
Rf value: 0.51 (silica gel, ethyl acetate/methanol = 9:1)
Mass spectrum (ESI+) : m/z = 616, 618 [M+H] +
(5) (JR) -4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- {2- [2- (methoxycarbonyl) -pyrrolidin-1-yl] -ethoxy} -7-cyclopentyloxy-quina- zoline
R£ value: 0.65 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI"): m/z = 527, 529 [M-H]"
(6) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl} -ethoxy) -7-cyclopentyloxy- quinazoline
R£ value: 0.54 (silica gel, methylene chloride/methanol/concen- trated aqueous ammonia = 90:10:0.1)
Mass spectrum (ESI") : m/z = 570, 572 [M-H]"
(7) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6 -cyclopentyloxy- 7- (2-{N- (2-hydroxy-2-methyl-prop-l-yl) -N- [(ethoxycarbonyl) - methyl] -amino} -ethoxy) -quinazoline
R£ value: 0.28 (silica gel, ethyl acetate) Mass spectrum (ESI"): m/z = 573, 575 [M-H]" (8) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6 -cyclopentyloxy-
7- [2- (6, 6 -dimethyl-2 -oxo-morpholin-4-yl) -ethoxy] -quinazoline (This compound was obtained by treatment of the compound prepared by example 3(7) with toluene-4-sulfonic acid in toluene.) Rf value: 0.23 (silica gel, ethyl acetate) Mass spectrum (ESI"): m/z = 527, 529 [M-H]"
(9) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6-cyclopentyloxy-
7- {2- [N- (2-oxo-tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} - quinazoline (The starting material 3-methylamino-dihydro- furan-2-one was prepared by reaction of 3-bromo-dihydro-furan- 2-one with N-methylbenzylamine and subsequent hydrogenolytic removal of the benzyl group)
Rf value: 0.42 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI+) : m/z = 515, 517 [M+H] +
(10) 4- [ (3 -bromo-phenyl) amino] -6- (2- {N- (2 -hydroxy-2 -methyl- prop-1-yl) -N- [ (ethoxycarbonyl) methyl] -amino} -ethoxy) -7-methoxy-quinazoline
(11) 4- [ (3-bromo-phenyl) amino] -6- [2- (6 , 6 -dimethyl-2-oxo-mor- pholin-4-yl) -ethoxy] -7-methoxy-quinazoline
R£ value: 0.33 (silica gel, ethyl acetate) Mass spectrum (ESI"): m/z = 499, 500 [M+H]"
(12) 4- [ (3-bromo-phenyl) amino] -6- {2- [N- (2-oxo-tetrahydrofuran- 4-yl) -N-methyl-amino] -ethoxy} -7-methoxy-quinazoline (The starting material 4-methylamino-dihydro-furan-2-one was prepared by reaction of 5H-furan-2-one with N-methyl-benzyl- amine and subsequent hydrogenolytic removal of the benzyl group)
R£ value: 0.38 (silica gel, ethyl acetate/methanol = 9:1) Mass spectrum (ESI"): m/z = 485, 487 [M-H]" Example 4
4- [ (3-bromophenyl) amino] -6- (3-{4- [ (ethoxycarbonyl) methyl] - piperaz n-1 -yl } -2-hydroxy-propyl oxy) -7-methoxy-qni aznl JΠP 0.16 ml of 1- [ (ethoxycarbonyl) methyl] -piperazine are added to 500 mg of 4- [ (3-bromophenyl) amino] -6-oxiranylmethoxy-7-methoxy- quinazoline in 5 ml ethanol . The reaction mixture is refluxed for about 6 hours. Then the mixture is concentrated by evaporation and the crude product is purified by chromatography on a silica gel column with ethyl acetate/ethanol/concentrated aqueous ammonia solution (9:1:0.1) as eluant. Yield: 97 mg of (14 % of theory) , melting point: 118-122°C Mass spectrum (El): m/z = 573, 575 [M] +
F.xampl e 5
4- [ (3-bromophenyl) amino] -6- {2- [4- (carboxymethyl) -piperazin-
1 -yl 1 ethoxy} -7-methoxy-qninazol ine
0.19 ml of IN sodium hydroxide solution are added to 100 mg of 4- [ (3-bromophenyl) amino] -6- (2-{4- [ (ethoxycarbonyl) methyl] - piperazin-1-yl}ethoxy) -7-methoxy-quinazoline in 0.30 ml of tetrahydrofuran. The reaction mixture is stirred for three hours at ambient temperature . Another 0.9 ml of IN sodium hydroxide solution are added and the mixture is stirred overnight . Then it is neutralised with IN hydrochloric acid and concentrated by evaporation. The solid residue is triturated with ethyl acetate and suction filtered.
Yield: 100 mg (contains about 0.5 equivalents sodium chloride), R£ value: 0.50 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1) Mass spectrum (ESI"): m/z = 514, 516 [M-H]"
The following compounds may also be obtained analogously to the foregoing Examples and other methods known from the literature: (1) 4- [ (3-bromophenyl) amino] -6- ({l- [ (methoxycarbonyl)'methyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(2) 4- [ (3-methylphenyl) amino] -6- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(3) 4- [ (3-chlorophenyl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(4) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- ( {l- [ (ethoxycarbo- nyDmethyl] -piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(5) 4- [ (indol-5-yl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(6) 4- [ (1-phenylethyl) amino] -6- ( {l- [ (ethoxycarbonyl) ethyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(7) 4- [ (3-ethynylphenyl) amino] -6- ( {1- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(8) 4- [ (3-bromophenyl) amino] -6- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(9) 4- [ (3-bromophenyl) amino] -6- ({l- [ (hexyloxycarbonyl) methyl] - piperidin-4-yl} ethoxy) -7-methoxy-quinazoline
(10) 4- [ (3-bromophenyl) amino] -6- ( {l- [2- (ethoxycarbonyl) ethyl] - piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(11) 4- [ (3-bromophenyl) amino] -6- ({l- [3- (ethoxycarbonyl) propyl] piperidin-4-yl} methoxy) -7-methoxy-quinazoline
(12) 4- [ (3-bromophenyl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] - piperidin-3 -yl}methoxy) -7-methoxy-quinazoline (13) 4- [ (3-bromophenyl) amino] -6- ({l- [ (ethoxycarbonyl)'methyl] - pyrrolidin-2 -yl}methoxy) -7-methoxy-quinazoline
(14) 4- [ (3-bromophenyl) amino] -6- ({l- [ (dimethoxyphosphoryl) - methyl] -piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(15) 4- [ (3-bromophenyl) amino] -6- [ (l-{ [ (methoxy) (methyl) phos- phoryl] methyl} -piperidin-4-yl) methoxy] -7-methoxy-quinazoline
(16) 4- [ (3-bromophenyl) amino] -6- ( {l- [1, 2-bis (ethoxycarbonyl) - ethyl] -piperidin-4-yl}methoxy) -7-methoxy-quinazoline
(17) 4- [ (3-bromophenyl) amino] -6-[(l-{l-[ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperidin-4-yl)methoxy] - 7-methoxy-quinazoline
(18) 4- [ (3-bromophenyl) amino] -6- (2-{l- [1- (methoxycarbonyl) - ethyl] -piperidin-4-yl}ethoxy) -7-methoxy-quinazoline
(19) 4- [ (3-bromophenyl) amino] -6- (2-{l- [ (methoxycarbonyl) methyl] -piperidin-4-yl}ethoxy) -7-methoxy-quinazoline
(20) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (methoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
(21) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
(22) 4- [ (3-bromophenyl) amino] -6- (2- {l- [ (ethoxycarbonyl) methyl] piperidin-4-yl}ethoxy) -7-methoxy-quinazoline
(23) 4- [ (3-bromophenyl) amino] -6- (2- {l- [1, 2-bis (ethoxycarbonyl) ethyl] -piperidin-4-yl}ethoxy) -7-methoxy-quinazoline
(24) 4- [ (3-bromophenyl) amino] -6- (2-{4- [1, 2-bis (ethoxycarbonyl) ethyl] -piperazin-l-yl}ethoxy) -7-methoxy-quinazoline (25) 4- [ (3-bromophenyl) amino] -6-[2-(4-{l-[ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperazin-1-yl) ethoxy] -7-methoxy-quinazoline
(26) 4- [ (3-bromophenyl) amino] -6- [2- (1- {l- [ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperidin-4-yl) ethoxy] -7-methoxy-quinazoline
(27) 4- [ (3-bromophenyl) amino] -6- {2- [2- (methoxycarbonyl) -pyrro- lidin-1-yl] ethoxy} -7-methoxy-quinazoline
(28) 4- [ (3-bromophenyl) amino] -6- {2- [2- (ethoxycarbonyl) -piperi- din-l-yl] ethoxy} -7-methoxy-quinazoline
(29) 4- [ (3-bromophenyl) amino] -6- (3-{l- [ (methoxycarbonyl) methyl] -piperidin-4-yl}propyloxy) -7-methoxy-quinazoline
(30) 4- [ (3 -bromophenyl) amino] -6- (3- { - [ (methoxycarbonyl) me- thyl] -piperazin-1-yl} ropyloxy) -7-methoxy-quinazoline
(31) 4- [ (3-bromophenyl) amino] -6- (3-{4- [ (ethoxycarbonyl) methyl] - piperazin-l-yl}propyloxy) -7-methoxy-quinazoline
(32) 4- [ (3-bromophenyl) amino] -6- (3-{l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}propyloxy) -7-methoxy-quinazoline
(33) 4- [ (3-bromophenyl) amino] -6- (3-{l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl} -2-hydroxy- ropyloxy) -7-methoxy-quinazoline
(34) 4- [ (3-bromophenyl) amino] -6- (3-{4- [ (ethoxycarbonyl) methyl] - piperazin-1-yl} -2-hydroxy-propyloxy) -7-methoxy-quinazoline
(35) 4- [ (3-methylphenyl) amino] -6- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -7-methoxy-quinazoline
(36) 4- [ (3-chlorophenyl) amino] -6- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -7-methoxy-quinazoline (37) 4- [ (indol-5-yl) amino] -6- (3- {4- [ (ethoxycarbonyl)methyl] - piperazin-1-yl}propyloxy) -7-methoxy-quinazoline
(38) 4- [ (1-phenylethyl) amino] -6- (3- {4- [ (ethoxycarbonyl) methyl] piperazin-l-yl}propyloxy) -7-methoxy-quinazoline
(39) 4- [ (3-bromophenyl) amino] -6-{3- [2- {methoxycarbonyl) - pyrrolidin-1-yl] propyloxy} -7-methoxy-quinazoline
(40) 4- [ (3-bromophenyl) amino] -6- {3- [3- (methoxycarbonyl) -4-me- thyl-piperazin-1-yl] propyloxy} -7-methoxy-quinazoline
(41) 4- [ (3-bromophenyl) amino] -6- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7-ethoxy-quinazoline
(42) 4- [ (3-bromophenyl) amino] -6- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -7- (2-methoxyethoxy) -quinazoline
(43) 4- [ (3-bromophenyl) amino] -6- (2-{l- [ (ethoxycarbonyl) methyl] piperidin-4-yl}ethoxy) -7- (2-methoxyethoxy) -quinazoline
(44) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] piperazin-l-yl}ethoxy) -7- (2-methoxyethoxy) -quinazoline
(45) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] piperazin-1-yl}ethoxy) -7-ethoxy-quinazoline
(46) 4- [ (3-bromophenyl) amino] -6- (3-{l- [ (ethoxycarbonyl) methyl] piperidin-4-yl}propyloxy) -7-ethoxy-quinazoline
(47) 4- [ (3-bromophenyl) amino] -6- (3 - {4- [ (ethoxycarbonyl) methyl] piperazin-1-yl}propyloxy) -7- (2-methoxyethoxy) -quinazoline
(48) 4- [ (3-bromophenyl) amino] -6- (3-{l- [ (dimethoxyphosphoryl) - methyl] -piperidin-4-yl}propyloxy) -7-methoxy-quinazoline (49) 4- [ (3-bromophenyl) amino] -6- (3- {4- [ (dimethoxyphosphoryl) - methyl] -piperazin-l-yl}propyloxy) -7-methoxy-quinazoline
(50) 4- [ (3-bromophenyl) amino] -6- [3- (4- {[ (methoxy) (ethyl)phos- phoryl] methyl} -piperazin-1-yl) propyloxy] -7-methoxy-quinazoline
(51) 4- [ (3-bromophenyl) amino] -6- [3- (1- {[ (methoxy) (ethyl)phos- phoryl] methyl} -piperidin-4-yl) propyloxy] -7-methoxy-quinazoline
(52) 4- [ (3-bromophenyl) amino] -6- (3-{4- [1, 2-bis (ethoxycarbonyl) - ethyl] -piperazin-l-yl}propyloxy) -7-methoxy-quinazoline
(53) 4- [ (3-bromophenyl) amino] -6- [3- (l-{l- [ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperidin-4-yl) propyloxy] - 7-methoxy-quinazoline
(54) 4- [ (3-bromophenyl) amino] -6- (4-{l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}butyloxy) -7-methoxy-quinazoline
(55) 4- [ (3-bromophenyl) amino] -6- (4- {4- [ (ethoxycarbonyl) methyl] - piperazin-l-yl}butyloxy) -7-methoxy-quinazoline
(56) 4- [ (3-bromophenyl) amino] -6- (2- {N- [ (ethoxycarbonyl) methyl] - N-methylamino}ethoxy) -7-methoxy-quinazoline
(57) 4- [ (3-bromophenyl) amino] -6- (2-{N,N-bis [ (ethoxycarbonyl) methyl] amino}ethoxy) -7-methoxy-quinazoline
(58) 4- [ (3-bromophenyl) amino] -6- (2-{N- [ (ethoxycarbonyl) methyl] - N-ethylamino}ethoxy) -7-methoxy-quinazoline
(59) 4- [ (3-bromophenyl) amino] -6- (2-{N- [ (ethoxycarbonyl) methyl] - N- (cyclopropylmethyl) -amino}ethoxy) -7-methoxy-quinazoline
(60) 4- [ (3-bromophenyl) amino] -6- (2- { [ (ethoxycarbonyl) methyl] - amino}ethoxy) -7-methoxy-quinazoline (61) 4- [ (3-bromophenyl) amino] -6- (2- {N- [ (ethoxycarbonyl) methyl] ■ N-cyclopropyl-amino}ethoxy) -7-methoxy-quinazoline
(62) 4- [ (3-bromophenyl) amino] -6- (2-{N- [ (methoxycarbonyl) methyl] -N-methylamino}ethoxy) -7-methoxy-quinazoline _ -
(63) 4- [ (3-bromophenyl) amino] -6- (3-{N- [ (methoxycarbonyl) methyl] -N-methylamino}propyloxy) -7-methoxy-quinazoline
(64) 4- [ (3-bromophenyl) amino] -6- (3- {N,N-bis [ (methoxycarbonyl) - methyl] amino}propyloxy) -7-methoxy-quinazoline
(65) 4- [ (3-bromophenyl) amino] -6- (3-{ [ (ethoxycarbonyl) methyl] - amino}propyloxy) -7-methoxy-quinazoline
(66) 4- [ (3-bromophenyl) amino] -6- (4-{N- [ (ethoxycarbonyl) methyl] ■ N-methylamino}butyloxy) -7-methoxy-quinazoline
(67) 4- [ (3-bromophenyl) amino] -6- (4- {N,N-bis [ (ethoxycarbonyl) methyl] amino}butyloxy) -7-methoxy-quinazoline
(68) 4- [ (3-bromophenyl) amino] -6- ({4- [ (methoxycarbonyl) methyl] - 2-oxo-morpholin-6-yl}methyloxy) -7-methoxy-quinazoline
(69) 4- [ (3-bromophenyl) amino] -6- [ (4-methyl-2-oxo-morpholin- 6-yl) methyloxy] -7-methoxy-quinazoline
(70) 4- [ (3-bromophenyl) amino] -6- [ (2-oxo-morpholin-6-yl) methyloxy] -7-methoxy-quinazoline
(71) 4- [ (4-amino-3 , 5-dibromo-phenyl) amino] -6- (3- {4- [ (methoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -7-methoxy-quinazoline
(72) 4- [ (4-amino-3 , 5-dibromo-phenyl) amino] -6- (3- {l- [ (methoxycarbonyl) methyl] -piperidin-4-yl}propyloxy) -7-methoxy-quinazoline (73) 4- [ (3-bromophenyl) amino] -6, 7-bis (2-{N- [ (ethoxycarbonyl) - methyl] -N-methylamino}ethoxy) -quinazoline
(74) 4- [ (3-bromophenyl) amino] -6, 7-bis (3- {N- [ (ethoxycarbonyl) methyl] -N-methylamino}propyloxy) -quinazoline
(75) 4- [ (3-bromophenyl) amino] -6- [3- (morpholino) propyloxy] - 7- [ (ethoxycarbonyl) methoxy] -quinazoline
(76) 4- [ (3-bromophenyl) amino] -6- [2- (morpholino) ethoxy] -7- [ (ethoxycarbonyl) methoxy] -quinazoline
(77) 4- [ (3-bromophenyl) amino] -7- ({l- [ (methoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(78) 4- [ (3-methylphenyl) amino] -7- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(79) 4- [ (3 -chlorophenyl) amino] -7- ( {1- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(80) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- ( {l- [ (ethoxycarbonyl) methyl] -piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(81) 4- [ (indol-5-yl) amino] -7- ( {l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(82) 4- [ (1-phenylethyl) amino] -7- ( {l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl }methoxy) -6-methoxy-quinazoline
(83) 4- [ (3-ethynylphenyl) amino] -7- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(84) 4- [ (3-bromophenyl) amino] -7- ({l- [ (ethoxycarbonyl) methyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline (85) 4- [ (3-bromophenyl) amino] -7- ({l- [ (hexyloxycarbonyl) methyl] • piperidin-4 -yl}methoxy) -6-methoxy-quinazoline
(86) 4- [ (3-bromophenyl) amino] -7- ( {l- [2- (ethoxycarbonyl) ethyl] - piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(87) 4- [ (3-bromophenyl) amino] -7- ({l- [3- (ethoxycarbonyl) ropyl] • piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(88) 4- [ (3-bromophenyl) amino] -7- ({l- [ (ethoxycarbonyl) methyl] - piperidin-3 -yl}methoxy) -6-methoxy-quinazoline
(89) 4- [ (3-bromophenyl) amino] -7- ( {l- [ (ethoxycarbonyl) methyl] - pyrrolidin-2-yl}methoxy) -6-methoxy-quinazoline
(90) 4- [ (3-bromophenyl) amino] -7- ( {l- [ (dimethoxyphosphoryl) methyl] -piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(91) 4- [ (3-bromophenyl) amino] -7- [ (l-{ [ (methoxy) (methyl) phos- phoryl] methyl} -piperidin-4-yl) methoxy] -6-methoxy-quinazoline
(92) 4- [ (3-bromophenyl) amino] -7- ( {l- [1, 2-bis (ethoxycarbonyl) - ethyl] -piperidin-4-yl}methoxy) -6-methoxy-quinazoline
(93) 4- [ (3-bromophenyl) amino] -7- [ (1- {l- [ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperidin-4-yl) methoxy] -
6-methoxy-quinazoline
(94) 4- [ (3-bromophenyl) amino] -7- (2-{l- [1- (methoxycarbonyl) - ethyl] -piperidin-4-yl}ethoxy) -6-methoxy-quinazoline
(95) 4- [ (3-bromophenyl) amino] -7- (2- {l- [ (methoxycarbonyl) methyl] -piperidin-4-yl}ethoxy) -6-methoxy-quinazoline
(96) 4- [ (3-bromophenyl) amino] -7- (2-{4- [ (methoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -6-methoxy-quinazoline (97) 4- [ (3-bromophenyl) amino] -7- (2- {4- [ (ethoxycarbonyl) methyl] • piperazin-1-yl}ethoxy) -6-methoxy-quinazoline
(98) 4- [ (3-bromophenyl) amino] -7- (2- {l- [ (ethoxycarbonyl) methyl] - piperidin-4 -yl}ethoxy) -6-methoxy-quinazoline
(99) 4- [ (3-bromophenyl) amino] -7- (2- {l- [1, 2-bis (ethoxycarbonyl) ethyl] -piperidin-4-yl}ethoxy) -6-methoxy-quinazoline
(100) 4- [ (3-bromophenyl) amino] -7- (2- {4- [1, 2-bis (ethoxycarbonyl) ethyl] -piperazin-l-yl}ethoxy) -6-methoxy-quinazoline
(101) 4- [ (3-bromophenyl) amino] -7- [2- (4-{l- [ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperazin-1-yl) ethoxy] -6-meth- oxy-quinazoline
(102) 4- [ (3-bromophenyl) amino] -7- [2- (l-{l- [ (ethoxycarbonyl) methyl] -2- (ethoxycarbonyl) -ethyl} -piperidin-4-yl) ethoxy] -6-meth- oxy-quinazoline
(103) 4- [ (3-bromophenyl) amino] -7- {2- [2- (methoxycarbonyl) -pyrro- lidin-1-yl] ethoxy} -6-methoxy-quinazoline
(104) 4- [ (3-bromophenyl) amino] -7- {2- [2- (ethoxycarbonyl) -piperi- din-l-yl] ethoxy} -6-methoxy-quinazoline
(105) 4- [ (3-bromophenyl) amino] -7- (3- {l- [ (methoxycarbonyl) methyl] -piperidin-4-yl}propyloxy) -6-methoxy-quinazoline
(106) 4- [ (3-bromophenyl) amino] -7- (3- {4- [ (methoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -6-methoxy-quinazoline
(107) 4- [ (3-bromophenyl) amino] -7- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl }propyloxy) -6-methoxy-quinazoline
(108) 4- [ (3-bromophenyl) amino] -7- (3- {l- [ (ethoxycarbonyl) methyl] -piperidin-4-yl}propyloxy) -6-methoxy-quinazoline (109) 4- [ (3-bromophenyl) amino] -7- (3- {l- [ (ethoxycarbonyl) methyl] -piperidin-4-yl} -2-hydroxy-propyloxy) -6-methoxy-quinazoline
(110) 4- [ (3-bromophenyl) amino] -7- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl} -2-hydroxy-propyloxy) -6-methoxy-quinazoline
(111) 4- [ (3-methylphenyl) amino] -7- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -6-methoxy-quinazoline
(112) 4- [ (3-chlorophenyl) amino] -7- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -6-methoxy-quinazoline
(113) 4- [ (indol-5-yl) amino] -7- (3- {4- [ (ethoxycarbonyl) methyl] - piperazin-1-yl}propyloxy) -6-methoxy-quinazoline
(114) 4- [ (1-phenylethyl) amino] -7- (3-{4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -6-methoxy-quinazoline
(115) 4- [ (3-bromophenyl) amino] -7- {3- [2- (methoxycarbonyl) - pyrrolidin-1-yl] propyloxy} -6-methoxy-quinazoline
(116) 4- [ (3-bromophenyl) amino] -7- {3- [3- (methoxycarbonyl) - 4-methyl-piperazin-l-yl] propyloxy} -6-methoxy-quinazoline
(117) 4- [ (3-bromophenyl) amino] -7- ({l- [ (ethoxycarbonyl) methyl] piperidin-4-yl}methoxy) -6-ethoxy-quinazoline
(118) 4- [ (3-bromophenyl) amino] -7- ( {l- [ (ethoxycarbonyl) methyl] piperidin-4-yl}methoxy) -6- (2-methoxyethoxy) -quinazoline
(119) 4- [ (3-bromophenyl) amino] -7- (2-{l- [ (ethoxycarbonyl) methyl] -piperidin-4-yl}ethoxy) -6- (2-methoxyethoxy) -quinazoline (120) 4- [ (3-bromophenyl) amino] -7- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}ethoxy) -6- (2-methoxyethoxy) -quinazoline
(121) 4- [ (3-bromophenyl) amino] -7- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}ethoxy) -6-ethoxy-quinazoline
(122) 4- [ (3-bromophenyl) amino] -7- (3- {l- [ (ethoxycarbonyl) methyl] -piperidin-4-yl}propyloxy) -6-ethoxy-quinazoline
(123) 4- [ (3-bromophenyl) amino] -7- (3- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}propyloxy) -6- (2-methoxyethoxy) -quinazoline
(124) 4- [ (3-bromophenyl) amino] -7- (3- {l- [ (dimethoxyphosphoryl) - methyl] -piperidin-4-yl}propyloxy) -6-methoxy-quinazoline
(125) 4- [ (3-bromophenyl) amino] -7- (3- {4- [ (dimethoxyphosphoryl) - methyl] -piperazin-1-yl}propyloxy) -6-methoxy-quinazoline
(126) 4- [ (3-bromophenyl) amino] -7- [3- (4- {[ (methoxy) (ethyl) phos- phoryl] methyl} -piperazin-1-yl) propyloxy] -6-methoxy-quinazoline
(127) 4- [ (3-bromophenyl) amino] -7- [3- (1- {[ (methoxy) (ethyl) phos- phoryl] methyl} -piperidin-4-yl) propyloxy] -6-methoxy-quinazoline
(128) 4- [ (3-bromophenyl) amino] -7- (3-{4- [1, 2-bis (ethoxycarbonyl) ethyl] -piperazin-1-yl}propyloxy) -6-methoxy-quinazoline
(129) 4- [ (3-bromophenyl) amino] -7- [3- (l-{l- [ (ethoxycarbonyl) - methyl] -2- (ethoxycarbonyl) -ethyl} -piperidin-4-yl) propyloxy] - 6-methoxy-quinazoline
(130) 4- [ (3 -bromophenyl) amino] -7- (4 - { 1- [ (ethoxycarbonyl) me- thyl] -piperidin-4-yl}butyloxy) -6-methoxy-quinazoline
(131) 4- [ (3-bromophenyl) amino] -7- (4- {4- [ (ethoxycarbonyl) me- thyl] -piperazin-l-yl}butyloxy) -6-methoxy-quinazoline (132) 4- [ (3-bromophenyl) amino] -7- (2-{N- [ (ethoxycarbonyl) methyl] -N-methylamino}ethoxy) -6-methoxy-quinazoline
(133) 4- [ (3-bromophenyl) amino] -7- (2- {N,N-bis [ (ethoxycarbonyl) - methyl] amino}ethoxy) -6-methoxy-quinazoline
(134) 4- [ (3-bromophenyl) amino] -7- (2-{N- [ (ethoxycarbonyl) methyl] -N-ethylamino}ethoxy) -6-methoxy-quinazoline
(135) 4- [ (3-bromophenyl) amino] -7- (2-{N- [ (ethoxycarbonyl) methyl] -N- (cyclopropylmethyl) -amino}ethoxy) -6-methoxy-quinazoline
(136) 4- [ (3-bromophenyl) amino] -7- (2-{ [ (ethoxycarbonyl) methyl] - amino}ethoxy) -6-methoxy-quinazoline
(137) 4- [ (3-bromophenyl) amino] -7- (2-{N- [ (ethoxycarbonyl) methyl] -N-cyclopropyl-amino}ethoxy) -6-methoxy-quinazoline
(138) 4- [ (3-bromophenyl) amino] -7- (2-{N- [ (methoxycarbonyl) methyl] -N-methylamino}ethoxy) -6-methoxy-quinazoline
(139) 4- [ (3-bromophenyl) amino] -7- (3-{N- [ (methoxycarbonyl) methyl] -N-methylamino}propyloxy) -6-methoxy-quinazoline
(140) 4- [ (3-bromophenyl) amino] -7- (3- {N,N-bis [ (methoxycarbonyl) - methyl] amino}propyloxy) -6-methoxy-quinazoline
(141) 4- [ (3-bromophenyl) amino] -7- (3- { [ (ethoxycarbonyl) methyl] - amino}propyloxy) -6-methoxy-quinazoline
(142) 4- [ (3-bromophenyl) amino] -7- (4- {N- [ (ethoxycarbonyl) methyl] -N-methylamino}butyloxy) -6-methoxy-quinazoline
(143) 4- [ (3-bromophenyl) amino] -7- (4- {N,N-bis [ (ethoxycarbonyl) - methyl] amino}butyloxy) -6-methoxy-quinazoline (144) 4- [ (3-bromophenyl) amino] -7- ({4- [ (methoxycarbonyl) methyl] - 2-oxo-morpholin-6-yl}methyloxy) -6-methoxy-quinazoline
(145) 4- [ (3-bromophenyl) amino] -7- [ (4-methyl-2-oxo-morpholin- 6-yl) methyloxy] -6-methoxy-quinazoline
(146) 4- [ (3-bromophenyl) amino] -7- [ (2-oxo-morpholin-6-yl) methyloxy] -6-methoxy-quinazoline
(147) 4- [ (4-amino-3 , 5-dibromo-phenyl) amino] -7- (3- {4- [ (methoxycarbonyl) methyl] -piperazin-l-yl}propyloxy) -6-methoxy-quinazoline
(148) 4- [ (4-amino-3 , 5-dibromo-phenyl) amino] -7- (3- {l- [ (methoxycarbonyl) methyl] -piperidin-4-yl}propyloxy) -6-methoxy-quinazoline
(149) 4- [ (3-bromophenyl) amino] -7- [3- (morpholino) propyloxy] - 6- [ (ethoxycarbonyl) methoxy] -quinazoline
(150) 4- [ (3-bromophenyl) amino] -7- [2- (morpholino) ethoxy] - 6- [ (ethoxycarbonyl) methoxy] -quinazoline
(151) 4- [ (3-bromophenyl) amino] -6- [2- (2-oxo-morpholin-4-yl) - ethoxy] -7-methoxy-quinazoline
(152) 4- [ (3-bromophenyl) amino] -6- [3- (2-oxo-morpholin-4-yl) ropyloxy] -7-methoxy-quinazoline
(153) 4- [ (3-bromophenyl) amino] -6- [2- (3-methyl-2-oxo-morpholin- 4-yl) ethoxy] -7-methoxy-quinazoline
(154) 4- [ (3-bromophenyl) amino] -6- [2- (5, 5-dimethyl-2-oxo-morpho- lin-4-yl) thoxy] -7-methoxy-quinazoline
(155) 4- [ (3-bromophenyl) amino] -6- (2-{4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}ethoxy) -7-cyclopropylmethoxy-quinazoline (156) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -7-cyclobutyloxy-quinazoline
(157) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -7-cyclopentyloxy-quinazoline
(158) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -7-cyclohexyloxy-quinazoline
(159) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}ethoxy) -7-cyclopentylmethoxy-quinazoline
(160) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl)methyl] -piperazin-l-yl}ethoxy) -7-cyclohexylmethoxy-quinazoline
(161) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (benzyloxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
(162) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (phenyloxycarbonyl) - methyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
(163) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (indan-5-yloxycar- bonyl) methyl] -piperazin-l-yl}ethoxy) -7-methoxy-quinazoline
(164) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (cyclohexyloxycarbonyl) methyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
(165) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (cyclohexylmethoxy- carbonyl) methyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
(166) 4- [ (3-bromophenyl) amino] -6-cyclopropylmethoxy-7- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-l-yl}ethoxy) quinazoline
(167) 4- [ (3-bromophenyl) amino] -6-cyclobutyloxy-7- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) quinazoline (168) 4- [ (3-bromophenyl) amino] -6-cyclopentyloxy-7- (2 - {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) quinazoline
(169) 4- [ (3-bromophenyl) amino] -6-cyclopentylmethoxy-7- (2- {4- [ (ethoxycarbonyl)methyl] -piperazin-1-yl}ethoxy) quinazoline
(170) 4- [ (3 -bromophenyl) amino] -6-cyclohexylmethoxy-7- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) quinazoline
(171) 4- [ (3-bromophenyl) amino] -6-cyclohexyloxy-7- (2- {4- [ (ethoxycarbonyl) methyl] -piperazin-1-yl}ethoxy) quinazoline
(172) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-methoxy-quinazoline
(173) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-cyclobutyloxy-quinazoline
(174) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentyloxy-quinazoline
(175) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-cyclohexyloxy-quinazoline
(176) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopropylmethoxy-quinazoline
(177) 4- [ (3 -chloro-4-fluoro-phenyl] amino] -6- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-cyclopentylmethoxy-quinazoline
(178) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -7-cyclohexylmethoxy-quinazoline
(179) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo- tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-methoxy- quinazoline (180) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo- tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-cyclopentyloxy-quinazoline
(181) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo- tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -7-cyclopentyl- methoxy-quinazoline
(182) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo- tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} -7-methoxy- quinazoline
(183) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo- tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} -7-cyclopentyloxy-quinazoline
(184) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- {2- [N- (2-oxo- tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} -7-cyclopentyl- methoxy-quinazoline
(185) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- [3- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -propyloxy] -7-methoxy-quinazoline
(186) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -6- [3- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline
(187) 4- [ (3-chloro-4-fluoro-phenyl) amino] -6- [3- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -propyloxy] -7-cyclopentylmethoxy-quina- zoline
(188) (R) -4- [ (1-phenyl-ethyl) amino] -6- [3- (6 , 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -7-cyclopentyloxy-quinazoline
(189) 4- [ (3-chloro-4-fluoro-phenyl) amino] -1 - [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-methoxy-quinazoline (190) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-cyclobutyloxy-quinazoline
(191) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentyloxy-quinazoline
(192) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- [2- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-cyclohexyloxy-quinazoline
(193) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopropylmethoxy-quinazoline
(194) 4- [ (3 -chloro-4-fluoro-phenyl] amino] -7- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-cyclopentylmethoxy-quinazoline
(195) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -7- [2- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -ethoxy] -6-cyclohexylmethoxy-quinazoline
(196) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo- tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -6-methoxy- quinazoline
(197) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo- tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -6-cyclopentyloxy-quinazoline
(198) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo- tetrahydrofuran-4-yl) -N-methyl-amino] -ethoxy} -6-cyclopentyl- methoxy-quinazoline
(199) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo- tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} -6-methoxy- quinazoline
(200) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo- tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} -6-cyclopentyloxy-quinazoline (201) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -7- {2- [N- (2-oxo- tetrahydrofuran-3-yl) -N-methyl-amino] -ethoxy} -6-cyclopentylmethoxy-quinazoline
(202) 4- [ (3 -chloro-4-fluoro-phenyl) amino] -7- [3- (6 , 6-dimethyl- 2-oxo-morpholin-4-yl) -propyloxy] -6-methoxy-quinazoline
(203) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- [3- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline
(204) 4- [ (3-chloro-4-fluoro-phenyl) amino] -7- [3- (6, 6-dimethyl- 2-oxo-morpholin-4-yl) -propyloxy] -6-cyclopentylmethoxy-quina- zoline
(205) (R) -4- [ (1-phenyl-ethyl) amino] -7- [3- (6, 6-dimethyl-2-oxo- morpholin-4-yl) -propyloxy] -6-cyclopentyloxy-quinazoline
Example 6
Coated tablets containing 75 mg of active substance
1 tablet core contains : active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1 ■ mg
230.0 mg
Preparation:
The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet- making machine to form tablets of the desired shape.
Weight of core: 230 mg die: 9 mm, convex
The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax. Weight of coated tablet: 245 mg.
Example 7
Tablets containing 100 mg of active subs ce
Composition:
1 tablet contains : active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg
220.0 mg
Method of Preparation:
The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50°C it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets .
Weight of tablet: 220 mg
Diameter: 10 mm, biplanar, facetted on both sides and notched on one side. Example 8
Tablets containing 150 mg of active substance
Composition:
1 tablet contains : active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate l.Q g
300.0 mg
Preparation:
The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45°C, are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
Weight of tablet: 300 mg die: 10 mm, flat
Example 9
Hard gelatine capsules containing 1 0 mg nf active substance
1 capsule contains : active substance 150.0 mg corn starch (dried approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3,0 mg approx. 420.0 mg Preparation;
The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.
Example 1Q
Supposi nries containing 150 mg of active substance
1 suppository contains : active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg
2,000.0 mg
Preparation:
After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.
Example 11
Suspension containing 5Q mg of active substance
100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g
70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml
Preparation:
The distilled water is heated to 70°C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.
5 ml of suspension contain 50 mg of active substance.
Example 12
Ampoules containing 10 mg active substance
Composition: active substance 10.0 mg
0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 ml
Preparat on:
The active substance is dissolved in the necessary amount of 0.01 N HC1, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Example 13
Ampoules containing 50 mg of active substance
Composition: active substance 50.0 mg
0.01 N hydrochloric acid q.s. double-distilled water ad 10.0 ml Preparation;
The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
F.yarnpl e 14
Capsul es for powder i nhal ati on conta i n i ng 5 mg of acti ve substance
1 capsule contains :
active substance 5.0 mg lactose for inhalation 1 . mg
20.0 mg
Preparation;
The active substance is mixed with lactose for inhalation. The mixture is packed into capsules in a capsule-making machine (weight of the empty capsule approx. 50 mg) .
weight of capsule: 70.0 mg size of capsule = 3
Example 15
Solution for inhalation for hand-held nebulisers containing 2.5 g active substance
1 spray contains :
active substance 2.500 mg benzalkonium chloride 0.001 mg IN hydrochloric acid q.s. ethanol/water (50/50) ad 15.000 mg Preparation:
The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50) . The pH of the solution is adjusted with IN hydrochloric acid. The resulting solution is filtered and transferred into suitable containers for use in hand-held nebulisers (cartridges) .
Contents of the container: 4.5 g

Claims

Patent Claims
1. Bicyclic heterocycles of general formula
Figure imgf000106_0001
wherein
Ra denotes a hydrogen atom or a Cx.t-alkyl group,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
R and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a Cx.4-alkyl, hydroxy, C^-alkoxy, C3_g-cycloalkyl, - C4.6-cycloalkoxy, C2.5-alkenyl or C2.5-alkynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a C3-5-alkenyloxy or C3.5-alkynyloxy group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C^-alkylsulphenyl, C1.4-alkylsulphinyl, C^-alkylsulpho- nyl, C1.4-alkylsulphonyloxy, trifluoromethylsulphenyl, tri- fluoromethylsulphinyl or trifluoromethylsulphonyl group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms, an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms,
a cyano or nitro group or an amino group optionally substituted by one or two C1-4-alkyl groups, whilst the substituents may be identical or different,
or Rx together with R2, if they are bound to adjacent carbon atoms, denote a -CH=CH-CH=CH, -CH=CH-NH or -CH=N-NH group and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
a C1-4-alkyl, trifluoromethyl or C1.4-alkoxy group,
Rc and Rd, which may be identical or different, each denote a hydrogen, fluorine or chlorine atom, a methoxy group or a methyl group optionally substituted by a methoxy, dimethyl- amino, diethylamino, pyrrolidino, piperidino or morpholino group,
X denotes a methine group substituted by a cyano group or a nitrogen atom,
A denotes an -0-C1-6-alkylene, -0-C4.7-cycloalkylene, -0-C1.3-alkylene-C3-7-cycloalkylene, -0-C4_7-cycloalkylene- Cx.3-alkylene or -0-C1-3-alkylene-C3.7-cycloalkylene-C^-alkylene group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
an -0-C1-6-alkylene group which is substituted by an R60-CO or R60-CO-C1-4-alkyl group, whilst R6 is as hereinafter defined and the oxygen atom of the abovementioned
Figure imgf000107_0001
groups in each case is linked to the bicyclic heteroaromatic ring,
an -0-C2.6-alkylene group which is substituted from position 2 onwards by a hydroxy, C^-alkoxy, amino, Cx_4-alkylamino, di- (C^-alkyl) -amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C1-4-alkyl) -piperazino group and the oxygen atom of the abovementioned-0-C2-6-alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
a -Cx_e-alkylene group,
an -NR4-C1.6-alkylene, -NR4-C3.7-cycloalkylene, -NR4 -Cx_2-alkylene- C3-7-cycloalkylene, -NR4-C3.7-cycloalkylene-C1.3-alkylene or -NR4-C^-alkylene-C3.7-cycloalkylene -Cx_3-alkylene group, whilst the -NR4- moiety of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, and
R4 denotes a hydrogen atom or a C1-4-alkyl group,
an oxygen atom, this being linked to a carbon atom of the group B, or
a NR4 group, the latter being linked to a carbon atom of the group B and R4 being as hereinbefore defined,
B denotes an R60-CO-alkylene-NR5, (R70-PO-OR8) -alkylene-NRs or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or
Figure imgf000108_0001
group, whilst
Rs denotes a hydrogen atom,
a C^-alkyl group which may be substituted by an R60-CO, (R70-PO-OR8) or (R70-PO-R9) group,
a C2.4-alkyl group which is substituted from position 2 by a hydroxy, C^-alkoxy, amino, x.t-alkylamino or di- (C^-al- kyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C1-4-alkyl) -imino group,
a C3_7-cycloalkyl or C3.7-cycloalkyl-C1.3-alkyl group,
R6, R7 and R8, which may be identical or different, in each case denote a hydrogen atom,
a C1-8-alkyl group which may be substituted from position 2 onwards by a hydroxy, C1.4-alkoxy, amino, C1.4-alkylamino or di- (CX_ -alkyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (C^-alkyl) - imino group,
a C4-7-cycloalkyl group optionally substituted by 1 or 2 methyl groups,
a C3-5-alkenyl or C3.5-alkynyl group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C3.7-cycloalkyl-C1-4-alkyl, aryl, aryl-C^-alkyl or RgCO-0- (ReCR£) group, whilst
Re and R£, which may be identical or different, in each case denote a hydrogen atom or a C^-alkyl group and
Rg denotes a C1-4-alkyl, C3.7-cycloalkyl, C1-4-alkoxy or C5-7-cycloalkoxy group,
and R9 denotes a C1-4-alkyl, aryl or aryl-C^-alkyl group,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO-C1-4-alkyl, bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -Cx.4-alkyl or (R70-PO-R9) - C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two R60-CO or
Figure imgf000110_0001
groups or by an R6OCO group and an
Figure imgf000110_0002
group wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO- C^-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined and
R10 denotes a hydrogen atom, a C1-4-alkyl, formyl, C^-alkylcarbonyl or C1-4-alkylsulphonyl group,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or
Figure imgf000110_0003
groups or by an R60-CO group and an R60-CO-Cx_4-alkyl group wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in each case in the 4 position by an R60-CO-C^-alkyl, bis- (RgO-CO) -C1-4-alkyl, (R70-PO-OR8) -Cx.4-alkyl or (R70-PO-R9) - C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group, which is substituted in the 4 position by an R60-CO-C1-4-alkyl, bis- (R60-CO) -C1-4-alkyl , (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C1-4-alkyl group and is additionally substituted at cyclic carbon atoms by one or two R60-CO or R60-CO-C1-4-alkyl groups or by an R60-CO group and an RgO-CO-Cx_4-alkyl group wherein R6 to R9 are as hereinbefore defined, a morpholino or homomorpholino group which is substituted in each case by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , RgO-CO-Cx.4-al- kyl, bis- (RgO-CO) -C1-4-alkyl, (R70-P0-OR8) -Cx_4-alkyl or (R70-PO-R9) -C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two R60-CO or R60-CO-C1.4-alkyl groups or by an R60-CO group and an R60-CO- Cx.i-alkyl group wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5 to 7-membered rings are in each case additionally substituted at a carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) ,
Figure imgf000111_0001
, (R70-PO-OR8) -Cx.4-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5 to 7-membered rings in each case are additionally substituted at carbon atoms by two R60-CO or
Figure imgf000111_0002
groups or by an R60-CO group and an
Figure imgf000111_0003
group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C1.4-alkyl, bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000111_0004
bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C-^-alkyl or (R70-P0-R9) -C^-alkyl group, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at carbon atoms by one or two RgO-CO or RgO-CO-C^-alkyl groups or by an R60-CO group and an RgO-CO-Cx.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 C1-2-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a
Figure imgf000112_0001
(R70-PO-OR8) -Cx.4-alkyl or (R70-PO-R9) -Cx.4-alkyl group, whilst R6 to R9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups in each case are linked to a carbon atom of the group A,
an R1XNR5 group wherein Rs is as hereinbefore defined and
R x denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydro- furan-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydro- pyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two methyl groups,
or A and B together denotes a hydrogen, fluorine or chlorine atom,
a C1-6-alkoxy group,
a C2-6-alkoxy group which is substituted from position 2 onwards by a hydroxy, C^-alkoxy, amino, Cx.4-alkylamino, di- (C1.4-al- kyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C1.4-alkyl) -piperazino, homopiperazino, 4- (Cx.4-alkyl) -homopiperazino or 1-imidazolyl group,
a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined, - Ill -
a Cx.g-alkoxy group which is substituted by an R60-CO, (R70-PO- OR8) or (R70-PO-R9) group, whilst R6 to R9 are as hereinbefore defined,
a C3.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group,
an amino, C1-4-alkylamino, di- (Cx_4-alkyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C1-4-alkyl) -piperazino, homopiperazino or 4- (C1-4-alkyl) -homopiperazino group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
C denotes an
Figure imgf000113_0001
kylene-C3.7-cycloalkylene, -0-C4_7-cycloalkylene-C1.3-alkylene or -0-C1.3-alkylene-C3.7-cycloalkylene-C1-3-alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
an -O-Ci.g-alkylene group which is substituted by an R60-CO or
Figure imgf000113_0002
group, whilst R6 is as hereinbefore defined and the oxygen atom of the abovementioned-0-C1-6-alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
an -0-C2.6-alkylene group which is substituted from position 2 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di- (C^-al- kyl) -amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C^-alkyl) -piperazino group and the oxygen atom of the abovementioned-0-C2.6-alkylene groups in each case is linked to the bicyclic heteroaromatic ring,
a -Cj.j-alkylene group,
an -NR4-C1.6-alkylene, -NR4-C3-7-cycloalkylene, -NR4-Cx_3-alkylene-
C3.7-cycloalkylene, -NR4-C3.7-cycloalkylene-C1.3-alkylene or
-NR4 -Cx_3-alkylene-C3.7-cycloalkylene-C1-3-alkylene group, whilst the -NR4- moiety of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring and R4 is as hereinbefore defined,
an oxygen atom, which is linked to a carbon atom of the group D, or
a NR4 group, where the latter is linked to a carbon atom of the group D and R4 is as hereinbefore defined,
D denotes an R60-CO-alkylene-NR5, (R70-PO-OR8) -alkylene-NR5 or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or R60-CO-C^-alkyl group, whilst Rs to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO-C1-4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -Cx.4-alkyl or (R70-PO-R9) - C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two R60-CO or R60-CO-Cx.4-alkyl groups or by an R6OCO group and an R60-CO-C1-4-alkyl group wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, (R70-PO-ORB) , (R70-PO-R9) , R60-CO- C1-4-alkyl, bis- (R60-CO) -C1.4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C1-4-alkyl group wherein R6 to R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or
Figure imgf000114_0001
groups or by an R60-CO group and an R60-CO-Cx.4-alkyl group wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in each case in the 4 position by an
Figure imgf000115_0001
bis- (RgO-CO)-C1-4-alkyl, (R,0-PO-ORB) -C1_4-alkyl or (R70-PO-R9) - C1-4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an
Figure imgf000115_0002
(R70-PO-OR8) -Cx.t-alkyl or (R70-P0-R9) -Cx.4-alkyl group and is additionally substituted at cyclic carbon atoms by one or two RgO-CO or RsO-CO-C1.4-alkyl groups or by an R60-CO group and an RgO-CO-C-^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a morpholino or homomorpholino group which is substituted in each case by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) ,
Figure imgf000115_0003
kyl, bis- (R60-CO) -C1-4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-Rg)
Figure imgf000115_0004
group wherein R6 to R9 are as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or RgO-CO-C^-alkyl groups or by an R60-CO group and an
Figure imgf000115_0005
group wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-CO, (R70-PO-OR8) , (R70-PO-R9) , R60-CO-C1-4-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO- OR8) -C^-alkyl or (R70-PO-R9) -Cx.4-alkyl group wherein R6 to R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by two R60-CO or
Figure imgf000116_0001
groups or by an R60-CO group and an RgO-CO-C1-4-alkyl group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C^,,-alkyl, bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000116_0002
.bis- (R60-CO) - C1.4-alkyl, (R70-PO-OR8) -C1-4-alkyl or (R70-PO-R9) -C^-alkyl group, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by one or two RgO-CO or
Figure imgf000116_0003
groups or by an R60-CO group and an R60-CO-C1.4-alkyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 C1-2-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a Cx.4-alkyl, R60-CO-C1.4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -Cx.4-alkyl group, whilst R6 to R9 are as hereinbefore defined and the abovementioned 2-oxo- morpholinyl groups are in each case linked to a carbon atom of the group C,
an R1XNR5 group wherein R5 and Rxx are as hereinbefore defined, or
C and D together denote a hydrogen, fluorine or chlorine atom,
a Ci.g-alkoxy group,
a C2.6-alkoxy group which is substituted from position 2 by a hydroxy, C1.4-alkoxy, amino, C1-4-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C^-alkyl) -piperazino, homopiperazino, 4- (C^-alkyl) -homopiperazino or 1-imidazolyl group,
a C1-4-alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined,
a Ci.g-alkoxy group which is substituted by an R60-CO, (R70-PO- OR8) or (R70-PO-R9) group, whilst R6 to R9 are as hereinbefore defined,
a C3.7-cycloalkoxy or C3-7-cycloalkyl-C1.4-alkoxy group
an amino, Cx_4-alkylamino, di- (C^-alkyl) -amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4- (C1.4-alkyl) -piperazino, homopiperazino or 4- (C1.4-al- kyl) -homopiperazino group,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, an (R70-PO-OR8) or (R70-PO-R9) group, or
that at least one of the groups B or D contains an optionally substituted 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran- 4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group, or
that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
whilst by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which may in each case be monosubstituted by R12, mono-, di- or trisubstituted by R13 or monosubstituted by R12 and additionally mono- or disub- stituted by R13, whilst the substituents may be identical or different and
R12 denotes a cyano, carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di- (Cx_4-alkyl) -aminocarbonyl, C1.4-alkylsulphenyl, Cx.4-alkylsulphinyl, Cx.4-alkylsulphonyl, hydroxy, C1.4-alkylsulphonyloxy, trifluoromethyloxy, nitro, amino, C1-4-alkylamino, di- (Cx.4-alkyl) -amino, C^-alkyl- carbonylamino, N- (C^-alkyl) -C^-alkylcarbonylamino, C^-al- kylsulphonylamino, N- (C^-alkyl) -C1.4-alkylsulphonylamino, aminosulphonyl, C1.4-alkylaminosulphonyl or di- (Cx_t- lkyl) - aminosulphonyl group or a carbonyl group which is substituted by a 5- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N- (Cx_4-alkyl) -imino group, and
R13 denotes a fluorine, chlorine, bromine or iodine atom, a C^-alkyl, trifluoromethyl or Cx.4-alkoxy group or
two groups R13, if they are bound to adjacent carbon atoms, together denote a 03.5-alkylene, methylenedioxy or 1,3-buta- dien-l,4-ylene group,
the tautomers, the stereoisomers and the salts thereof.
2. Bicyclic heterocycles of general formula I according to claim 1, wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms or
Rx together with R2, if they are bound to adjacent carbon atoms, denote a -CH=CH-CH=CH, -CH=CH-NH or -CH=N-NH group and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an
Figure imgf000119_0001
kylene-C3.7-cycloalkylene, -0-C4_7-cycloalkylene-C1.3-alkylene or -0-C1.3-alkylene-C3.7-cycloalkylene-C1_3-alkylene group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, an -0-C2.4-alkylene group which is substituted from position 2 onwards by a hydroxy group, whilst the oxygen atom of the abovementioned-0-C2_4-alkylene groups in each case is linked to the bicyclic heteroaromatic ring, or
an oxygen atom, this being linked to a carbon atom of the group B,
B denotes an R60-CO-alkylene-NR5, (R70-P0-0R8) -alkylene-NR5 or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 4 carbon atoms, may additionally be substituted by one or two C1-2-alkyl groups or by an R60-CO or R60-CO-C1.2-alkyl group, whilst
R5 denotes a hydrogen atom,
a C1-4-alkyl group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 by a hydroxy or C^-alkoxy group,
a C3.6-cycloalkyl or C3-g-cycloalkyl-C1.3-alkyl group,
R6, R7 and R8, which may be identical or different, in each case denote a hydrogen atom,
a C-L.o-alkyl group which may be substituted from position 2 onwards by a hydroxy, C1-4-alkoxy or di- (C1-4-alkyl) -amino group or by a 4- to 7-membered alkyleneimino group, whilst in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group in the 4 position may be replaced by an oxygen atom or by an N- (C^-alkyl) -imino group,
a C4.6-cycloalkyl group, a C3.s-alkenyl or C3.5-alkynyl group, whilst the unsaturated moiety may not be linked to the oxygen atom,
a C3.g-cycloalkyl-Ci.4-alkyl, aryl, aryl-C1-4-alkyl or RgCO-0- (ReCR£) group, whilst
Re and Rf, which may be identical or different, in each case denote a hydrogen atom or a CX.Λ-alkyl group and
Rg denotes a C^-alkyl, C3.6-cycloalkyl, Cx.4-alkoxy or C5.6-cycloalkoxy group,
and R9 denotes a C^-alkyl group,
a 4- to 7-membered alkyleneimino group which is substituted by an R60-CO, R60-CO-C1-4-alkyl or bis- (R60-CO) -Cx.4-alkyl group wherein R6 is as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two RgO-CO or
Figure imgf000121_0001
groups wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-C0,
Figure imgf000121_0002
or bis- (R60-CO) - C^-alkyl group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or
Figure imgf000121_0003
groups wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which in each case is substituted in the 4 position by an R60-CO-C1-4-alkyl, bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an R60-CO-C^-alkyl or bis- (R60-CO) -Cx.4-alkyl group and is additionally substituted at cyclic carbon atoms by one or two R60-CO or R60-CO-C1-4-alkyl groups wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted in each case by an R60-CO,
Figure imgf000122_0001
or bis- (R60-CO) - C^-alkyl group wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or
Figure imgf000122_0002
groups wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-CO, R60-CO-C1.4-alkyl or bis- (RgO-CO) -C^-alkyl group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by two R60-CO or
Figure imgf000122_0003
groups wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C1.4-alkyl, bis- (R60-CO) - C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000122_0004
or bis- (RgO-CO) -C^-alkyl group, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by one or two R60-CO or
Figure imgf000123_0001
groups wherein R6 is as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 Cx_2-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a
Figure imgf000123_0002
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups in each case are linked to a carbon atom of the group A,
an R13NR5 group wherein R5 is as hereinbefore defined and
R x denotes a 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydro- furan-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydro- pyran-4-yl or 2-oxo-tetrahydropyran-5-yl group optionally substituted by one or two methyl groups,
or A and B together denote a hydrogen atom,
a C1-4-alkoxy group,
a C2-4-alkoxy group which is substituted from position 2 by a hydroxy, C^-alkoxy, amino, C1-4-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C^-alkyl) -piperazino group,
a C^-alkoxy group which is substituted by a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R10, whilst R10 is as hereinbefore defined,
a C1-4-alkoxy group which is substituted by an R60-CO group, whilst R6 is as hereinbefore defined, a C4.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group,
C denotes an -O-C^-alkylene, -0-C4.7-cycloalkylene, -O-C^-j-al- kylene-C3.7-cycloalkylene, -0-C4.7-cycloalkylene-C1.3-alkylene or -0-C1.3-alkylene-C3,7-cycloalkylene-C1.3-alkylene group, whilst the oxygen atom of the abovementioned group in each case is linked to the bicyclic heteroaromatic ring,
an -0-C2.4-alkylene group which is substituted from position 2 onwards by a hydroxy group, whilst the oxygen atom of the abovementioned-0-C2-4-alkylene groups in each case is linked to the bicyclic heteroaromatic ring, or
an oxygen atom, which is linked to a carbon atom of the group D,
D denotes an R60-CO-alkylene-NRS, (R70-PO-OR8) -alkylene-NR5 or (R70-PO-R9) -alkylene-NR5 group wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 4 carbon atoms, may additionally be substituted by one or two Cx,2-alkyl groups or by an R60-CO or
Figure imgf000124_0001
group, whilst Rs to R9 are as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by an RgO-CO,
Figure imgf000124_0002
group wherein R6 is as hereinbefore defined,
a 4- to 7-membered alkyleneimino group which is substituted by two RgO-CO or RgO-CO-Ci.4-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an R60-CO, R60-CO-C1-4-alkyl or bis- (R60-CO) - C1-4-alkyl group wherein R6 and R10 are as hereinbefore defined, a piperazino or homopiperazino group which is substituted in the 4 position by the group R10 and is additionally substituted at cyclic carbon atoms by two R60-CO or R60-CO-Cx.4-alkyl groups wherein R6 and R10 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in each case in the 4 position by an R60-CO-G^-alkyl, bis- (RgO-CO) -C^-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) - C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a piperazino or homopiperazino group which is substituted in the 4 position by an R60-CO-C^-alkyl or bis- (R60-CO) -C^-alkyl group and is additionally substituted at cyclic carbon atoms by one or two R60-CO or
Figure imgf000125_0001
groups wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted in each case by an R60-CO, R60-CO-Cx_4-alkyl, or bis- (R60-CO) - C^-alkyl group wherein R6 is as hereinbefore defined,
a morpholino or homomorpholino group which is substituted by two RgO-CO or
Figure imgf000125_0002
groups wherein R6 is as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings in each case are additionally substituted at a carbon atom by an R60-CO,
Figure imgf000125_0003
or bis- (RgO-CO) -C^-alkyl group wherein R6 and R10 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by the group R10, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by two R60-CO or RsO-CO- X.Λ-alkyl groups wherein R6 and R10 are as hereinbefore defined, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C^-alkyl, bis- (R60-CO) - C1-4-alkyl, (R70-PO-OR8) -C^-alkyl or (R70-PO-R9) -C^-alkyl group wherein R6 to R9 are as hereinbefore defined,
a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000126_0001
or bis- (RgO-CO) -C-^-alkyl group, whilst the abovementioned 5- to 7-membered rings are in each case additionally substituted at carbon atoms by one or two R60-CO or
Figure imgf000126_0002
groups wherein R6 is as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 to 4 C^-alkyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a hydrogen atom, by a
Figure imgf000126_0003
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C,
an R^NRg group wherein R5 and R are as hereinbefore defined, or
C and D together denote a hydrogen atom,
a Cx.4-alkoxy group,
a C2.4-alkoxy group which is substituted from position 2 by. a hydroxy, C1-4-alkoxy, amino, C^-alkylamino, di- (C^-alkyl) - amino, pyrrolidino, piperidino, morpholino, piperazino or 4- (C1-4-alkyl) -piperazino group,
a C^-alkoxy group which is substituted by a pyrrolidinyl or piperidinyl group substituted in the 1 position by the group R10, whilst Rx0 is as hereinbefore defined, a C1-4-alkoxy group which is substituted by an RεO-CO group, whilst R6 is as hereinbefore defined,
a C4.7-cycloalkoxy or C3.7-cycloalkyl-C1.4-alkoxy group
with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R70-PO-OR8) or (R70-PO-R9) group, or
that at least one of the groups B or D contains an optionally substituted 2-oxo-tetrahydrofuran-3-yl, 2-oxo-tetrahydrofuran- 4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group, or
that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
whilst by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which in each case may be monosubstituted by R12, mono- or disubstituted by R13 or monosubstituted by R12 and additionally mono- or disubstituted by R13, whilst the substituents may be identical or different and
R12 denotes a cyano, C1-2-alkoxycarbonyl, aminocarbonyl, C^-alkylaminocarbonyl, di- (C1-2-alkyl) -aminocarbonyl, Cx_2 -alkylsulphenyl, C1-2-alkylsulphinyl, C^-alkylsulphonyl, hydroxy, nitro, amino, C1-4-alkylamino or di- (C^-alkyl) -amino group and
R13 denotes a fluorine, chlorine, bromine or iodine atom, a Cx_ 2-alkyl, trifluoromethyl or C^-alkoxy group or two groups R13, if they are bound to adjacent carbon atoms, together denote a C -alkylene, methylenedioxy or 1,3-buta- dien-l,4-ylene group,
the tautomers, stereoisomers and salts thereof.
2. Bicyclic heterocycles of general formula I according to claim 1, wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
B denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst R5 denotes a hydrogen atom,
a C-^-alkyl group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 onwards by a hydroxy group,
a C3.6-cycloalkyl or C3.6-cycloalkylmethyl group and
R6 denotes a hydrogen atom,
a Cj.g-alkyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, eyelohexylmethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCR£) group, whilst
Re denotes a hydrogen atom or a C^-alkyl group,
R£ denotes a hydrogen atom and
Rg denotes a C^-alkyl, cyclopentyl, cyclohexyl, C^-alkoxy, cyclopentyloxy or cyclohexyloxy group,
a pyrrolidino or piperidino group which is substituted by an RgO-CO or RgO-CO-Ci.j-alkyl group wherein R6 is as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by two RgO-CO or RgO-CO-C^-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or RgO-CO-C^-alkyl group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group, a piperazino group which is substituted in the 4 position by an R60-CO-Cn-alkyl, bis- (R60-CO) -C^-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 is as hereinbefore defined,
R7 and R8, which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCRf) group, whilst
Re to Rg are as hereinbefore defined,
and R9 denotes a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an R60-CO-C1-2-alkyl group and additionally at a cyclic carbon atom by an R60-CO or R60-CO- Cx_2-alkyl group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or R60-CO- C^-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an RgO-CO-C^-alkyl , bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups ,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or
Figure imgf000130_0001
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups in each case are linked to a carbon atom of the group A,
a RX1N (C1-2-alkyl) group wherein R1X denotes a 2-oxo-tetrahydrofuran-3 -yl or 2-oxo-tetrahydrofuran-4-yl group, or A and B together denote a hydrogen atom, a methoxy, ethoxy or 2-methoxy-ethoxy group,
a C^-alkoxy group which is substituted by an R60-CO group, whilst R6 is as hereinbefore defined,
a C4.6-cycloalkoxy or C3.g-cycloalkyl-C1.3-alkoxy group,
C denotes an -O-C^-alkylene or -0-CH2-CH(OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
D denotes an R60-CO-alkylene-NRs group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst Rs and R6 are as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by an RgO-CO or RgO-CO-Ci.j-alkyl group wherein R6 is as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by two RgO-CO or
Figure imgf000131_0001
groups wherein R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or
Figure imgf000131_0002
group wherein R6 and R10 are as hereinbefore defined,
a piperazino group which is substituted in the 4 position by an
Figure imgf000131_0003
bis- (R60-CO) -C1-4-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined, a piperazino group which is substituted in the 4 position by an
Figure imgf000132_0001
group and additionally at a cyclic carbon atom by an R60-CO or
Figure imgf000132_0002
group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or R60-CO- C-^-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R60-CO-C^-alkyl, bis- (R60-CO) -C^-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by 1 or 2 methy1 groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or R60-CO-C1_2-alkyl group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C, or
a R1:LN (C-L.j.-alkyl) group wherein Rxx denotes a 2-oxo-tetrahydrofuran-3 -yl or 2-oxo-tetrahydrofuran-4-yl group, or
C and D together denote a hydrogen atom, a methoxy, ethoxy or 2-methoxy-ethoxy group,
a C^-alkoxy group which .is substituted by an R60-CO group, whilst R6 is as hereinbefore defined,
a C4.6-cycloalkoxy or
Figure imgf000132_0003
group
with the proviso that at least one of the groups B or D or A together with B or C together with D contains an optionally substituted 2-oxo-morpholinyl group, a (R70-PO-OR8) or (R70-PO-R9) group, or that at least one of the groups A, B, C or D or A together with B or C together with D contains an R60-CO group and additionally one of the groups A, B, C or D or A together with B or C together with D contains a primary, secondary or tertiary amino function, whilst the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
the tautomers, stereoisomers and salts thereof.
3. Bicyclic heterocycles of general formula I according to claim 1, wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
R-L and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
B denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst
R5 denotes a hydrogen atom,
a C^-alkyl group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 onwards by a hydroxy group,
a C3.6-cycloalkyl or C3.6-cycloalkylmethyl group and
Rg denotes a hydrogen atom,
a Ci.g-alkyl, cyclopentyl, cyclopentylmethyl , cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 5-indanyl or RgC0-0- (ReCRf) group, whilst
Re denotes a hydrogen atom or a C1.4-alkyl group,
Rf denotes a hydrogen atom and
Rg denotes a C^-alkyl, cyclopentyl, cyclohexyl, Cj^-alkoxy, cyclopentyloxy or cyclohexyloxy group,
a pyrrolidino or piperidino group which is substituted by an R60-CO or RgO-CO-Ci.j-alkyl group wherein R6 is as hereinbefore defined,
a pyrrolidino or piperidino group which is substituted by two RgO-CO or R60-CO-C1-2-alkyl groups wherein R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or
Figure imgf000135_0001
group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RgO-CO-C^-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 is as hereinbefore defined,
R7 and R8, which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCRf) group, whilst
Re to Rg are as hereinbefore defined,
and R9 denotes a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RgO-CO-C^-alkyl group and is additionally substituted at a cyclic carbon atom by an R60-CO or
Figure imgf000135_0002
group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or RβO-CO- C^-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an RgO-CO-C^-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined, -
a 2-oxo-morpholino group which may be substituted by 1 or 2 methy1 groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or
Figure imgf000135_0003
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpho- linyl groups in each case are linked to a carbon atom of the group A, or
a R11N(C1.2-alkyl) group wherein Rxx denotes a 2-oxo-tetrahydrofuran-3 -yl or 2-oxo-tetrahydrofuran-4-yl group, and
C and D together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C4.6-cycloalkoxy or C3.6-cycloalkyl-C1.3-alkoxy group,
the tautomers, the stereoisomers and the salts thereof.
4. Bicyclic heterocycles of general formula I according to claim 1, wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl, benzyl or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom,
a methyl, trifluoromethyl, methoxy, ethynyl or cyano group and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A and B together denote a hydrogen atom, a methoxy, ethoxy, 2-methoxy-ethoxy, C4.g-cycloalkoxy or
Figure imgf000136_0001
group, C denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring, and
D denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 or 2 carbon atoms, may additionally be substituted by an R60-CO or R60-CO- methyl group, whilst
R5 denotes a hydrogen atom,
a C^-alkyl group which may be substituted by an R60-CO group,
a C2.4-alkyl group which is substituted from position 2 by a hydroxy group,
a C3.6-cycloalkyl or C3.6-cycloalkylmethyl group and
R6 denotes a hydrogen atom,
a C^g-alkyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, eyelohexylmethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCR£) group, whilst
Re denotes a hydrogen atom or a C^-alkyl group,
Rf denotes a hydrogen atom and
Rg denotes a Cx.4-alkyl, cyclopentyl, cyclohexyl, C^-alkoxy, cyclopentyloxy or cyclohexyloxy group,
a pyrrolidino or piperidino group which is substituted by an RgO-CO or RgO-CO-C^j-alkyl group wherein R6 is as hereinbefore defined, a pyrrolidino or piperidino group which is substituted by two RgO-CO or RgO-CO-Ci.j-alkyl groups wherein Rs is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by the group R10 and additionally at a cyclic carbon atom by an RgO-CO or RgO-CO-C1-2-alkyl group wherein R6 is as hereinbefore defined and
R10 denotes a hydrogen atom, a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RgO-CO-C^-alkyl, bis- (R60-CO) -C^-alkyl, (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 is as hereinbefore defined,
R7 and R8, which may be identical or different, in each case denote a hydrogen atom, a methyl, ethyl, phenyl, benzyl, 5-indanyl or RgCO-0- (ReCR£) group, whilst
Re to Rg are as hereinbefore defined,
and R9 denotes a methyl or ethyl group,
a piperazino group which is substituted in the 4 position by an RgO-CO-Ci.j-alkyl group and is additionally substituted at a cyclic carbon atom by an R60-CO or
Figure imgf000138_0001
group wherein R6 is as hereinbefore defined,
a morpholino group which is substituted by an R60-CO or R60-CO- CjL.j-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R60-CO-C1-4-alkyl, bis- (R60-CO) -C^-alkyl , (R70-PO-OR8) -methyl or (R70-PO-R9) -methyl group wherein R6 to R9 are as hereinbefore defined, a 2-oxo-morpholino group which may be substituted by 1 or 2 methyl groups,
a 2-oxo-morpholinyl group which is substituted in the 4 position by a methyl, ethyl or
Figure imgf000139_0001
group, whilst R6 is as hereinbefore defined and the abovementioned 2-oxo-morpholinyl groups are in each case linked to a carbon atom of the group C, or
a RxlN (Cx.2-alkyl) group wherein Rxl denotes a 2-oxo-tetrahydrofuran-3 -yl or 2-oxo-tetrahydrofuran-4-yl group,
the tautomers, stereoisomers and salts thereof.
5. Bicyclic heterocycles of general formula I according to claim 1, wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst
Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A denotes an -O-C^-alkylene or -0-CH2-CH (OH) -CH2 group, whilst the oxygen atom of the abovementioned groups in each case is linked to the bicyclic heteroaromatic ring,
B denotes an R60-CO-CH2-NR5 group wherein R5 denotes a hydrogen atom or a methyl group which may be substituted by an R60-CO group, or
a C2.4-alkyl group substituted from position 2 onwards by a hydroxy group, and
Rg denotes a hydrogen atom, a methyl or ethyl group,
a pyrrolidino or piperidino group which is substituted by an RgO-CO group, whilst R6 is as hereinbefore defined,
a piperazino group which is substituted in the 4 position by an R60-CO-CH2 or bis- (RsO-CO) -C^-alkyl group, whilst R6 is as hereinbefore defined,
a pyrrolidinyl or piperidinyl group substituted in the 1 position by an R60-CO-CH2 group, whilst R6 is as hereinbefore defined,
a 2-oxo-morpholino group which may be substituted by one or two methyl groups, or
a RlaN (Cx.2-alkyl) group wherein Rxl denotes a 2-oxo-tetrahydro- furan-3-yl or 2-oxo-tetrahydrofuran-4-yl group, and
C and D together denote a methoxy, C4.6-cycloalkoxy or C3.6-cycloalkylmethoxy group,
the tautomers, stereoisomers and salts thereof.
7. Bicyclic heterocycles of general formula I according to claim 1, wherein
Ra denotes a hydrogen atom,
Rb denotes a phenyl group wherein the phenyl nucleus is substituted in each case by the groups Rx to R3, whilst Rx and R2, which may be identical or different, each denote a hydrogen, fluorine, chlorine or bromine atom and
R3 denotes a hydrogen atom,
Rc and Rd in each case denote a hydrogen atom,
X denotes a nitrogen atom,
A and B together denote a C4.6-cycloalkoxy or C3.6-cycloalkyl- methoxy group,
C denotes an -0-CH2CH2 group, whilst the oxygen atom of the abovementioned group is linked to the bicyclic heteroaromatic ring,
D denotes an R60-CO-CH2-NR5 group wherein
R5 denotes a C2.4-alkyl group substituted from position 2 onwards by a hydroxy group, and
R6 denotes a methyl or ethyl group,
a 2-oxo-morpholino group which may be substituted by one or two methyl groups, or
a RxlN(C1-2-alkyl) group wherein R x denotes a 2-oxo-tetrahydrofuran-3 -yl or 2-oxo-tetrahydrofuran-4-yl group,
the tautomers, stereoisomers and salts thereof.
8. The following bicyclic heterocycles of general formula I according to claim 1 :
(1) 4- (3-chloro-4-fluorophenylamino) -6- {3- [4- (methoxycarbonyl- methyl) -1-piperazinyl] propyloxy} -7-methoxy-quinazoline, (2) 4- [ (3-bromophenyl) amino] -6- (2- {4- [ (ethoxycarbonyl) methyl] - piperazin-1-yl}ethoxy) -7-methoxy-quinazoline,
(3) ( S) -4- [ (3-bromophenyl) amino] -6- [3- (2-methoxycarbonyl- pyrrolidin-1-yl) propyloxy] -7-methoxy-quinazoline,
(4) 4- [ (3-bromophenyl) amino] -6- (3- {4- [ (ethoxycarbonyl)methyl] - piperazin-1-yl} -2-hydroxy-propyloxy) -7-methoxy-quinazoline,
(5) (S) -4- [ (3-bromophenyl) amino] -6- ( {l- [ (ethoxycarbonyl) methyl] -pyrrolidine-2-yl}methoxy) -7-methoxy-quinazoline and
(6) 4- [ (3-bromophenyl) amino] -6- (2- {4- [1, 2 bis (methoxycarbonyl) - ethyl] -piperazin-1-yl}ethoxy) -7-methoxy-quinazoline
and the salts thereof .
9. Physiologically acceptable salts of the compounds according to claims 1 to 8 with inorganic or organic acids of bases .
10. Pharmaceutical compositions containing a compound according to claims 1 to 8 or a physiologically acceptable salt according to claim 9 optionally together with one or more inert carriers and/or diluents .
11. Use of a compound according to at least one of claims 1 to 9 for preparing a pharmaceutical compositions which is suitable for treating benign or malignant tumours, for preventing and treating diseases of the airways and lungs, for treating polyps, diseases of the gastro-intestinal tract, the bile ducts and gall bladder and the kidneys and skin.
12. Process for preparing a pharmaceutical composition according to claim 10, characterised in that a compound according to at least one of claims 1 to 9 is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
13. Process for preparing the compounds of general formula I according to claims 1 to 9, characterised in that
a) a compound of general formula
R-, R, a\ /
Figure imgf000143_0001
wherein
Ra to Rd, C, D and X are defined as in claims 1 to 8 and
U denotes an oxygen atom or an R4N group, whilst R4 is defined as in claims 1 to 8, is reacted with a compound of general formula
Figure imgf000143_0002
wherein
B is defined as in claims 1 to 8,
A' denotes one of the optionally substituted alkylene, cycloalkylene, alkylene-cycloalkylene, cycloalkylene-alkylene or alkylene-cycloalkylene-alkylene moieties mentioned in claims 1 to 8 for the group A, which are linked to the heteroaromatic group via an oxygen atom or via an NR4 group, and Zx denotes a leaving group, or b) a compound of general formula
Figure imgf000144_0001
wherein
Ra to Ra, A, B and X are defined as in claims 1 to 8 and
W denotes an oxygen atom or an R4N group, whilst R4 is defined as in claims 1 to 8, is reacted with a compound of general formula
- D , (V)
wherein
D is defined as in claims 1 to 8 ,
C denotes one of the optionally substituted alkylene, cycloalkylene, alkylene-cycloalkylene, cycloalkylene-alkylene or alkylene-cycloalkylene-alkylene moieties mentioned above for the group C, which are linked to the heteroaromatic group via an oxygen atom or via an NR4 group, and Z2 denotes a leaving group, or
c) in order to prepare a compound of general formula I whereir A is defined as in claims 1 to 8 with the exception of the oxygen atom and the -NR4 group : a compound of general formula
Figure imgf000145_0001
wherein
Ra to Rd, C, D and X are defined as in claims 1 to 8 and
A" has the meanings given for A in claims 1 to 8 with the exception of the oxygen atom and the -NR4 group and
Z3 denotes a leaving group or together with a hydrogen atom of an adjacent hydrocarbon group denotes an oxygen atom, is reacted with a compound of general formula
H - B , (VII)
wherein
B is defined as in claims 1 to 8, or
d) in order to prepare a compound of general formula I wherein C is defined as in claims 1 to 8 with the exception of the oxygen atom and the -NR4 group:
a compound of general formula
R.
Figure imgf000145_0002
wherein
C" has the meanings given for C in claims 1 to 8 with the exception of the oxygen atom and the -NR4 group and Z4 denotes a leaving group or together with a hydrogen atom of an adjacent hydrocarbon group denotes an oxygen atom, is reacted with a compound of general formula
H - D (IX)
wherein
D is defined as in claims 1 to 8, or
e) in order to prepare a compound of general formula I wherein B denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or RgO-CO-Cx_2-alkyl group, a piperazino or homopiperazino group substituted in the 4 position by an R60-CO-C1-4-alkyl or bis- (R60-CO) -C1-4-alkyl group or a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an R60-CO-C1-4-alkyl or bis- (RgO-CO) -C^-alkyl group, whilst in each case R5 and R6 are defined as in claims 1 to 8 :
a compound of general formula
Ra Rb
Figure imgf000146_0001
wherein
Ra to Rd, A, C, D and X are defined as in claims 1 to 8 and
B' denotes an R5NH group wherein Rs is defined as in claims 1 to 8 , a piperazino or homopiperazino group unsubstituted in the
4 position, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group unsubstituted in the 1 position, is reacted with a compound of general formula R60-CO-alkylene-Z5 , (XI )
wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or R60-CO-Cx_2-alkyl group, whilst R6 in each case is defined as in claims 1 to 8, and Z5 denotes an exchangeable group, or
f) in order to prepare a compound of general formula I wherein D denotes an R60-CO-alkylene-NR5 group wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two C^-alkyl groups or by an R60-CO or
Figure imgf000147_0001
group, a piperazino or homopiperazino group substituted in the 4 position by an R60-CO-Cx.4-alkyl or bis- (R60-CO) -C^-alkyl group or a pyrrolidinyl, piperidinyl or hexahydroazepinyl group substituted in the 1 position by an
Figure imgf000147_0002
or bis- (RgO-CO) -C1-4-alkyl group, whilst in each case R5 and R6 are defined as in claims 1 to 8 :
a compound of general formula
Figure imgf000147_0003
wherein
Ra to Rd, A to C and X are defined as in claims 1 to 8 and
D" denotes an RSNH group wherein R5 is defined as in claims 1 to 8, a piperazino or homopiperazino group unsubstituted in the
4 position, a pyrrolidinyl, piperidinyl or hexahydroazepinyl group unsubstituted in the 1 position, is reacted with a compound of general formula
R60-CO-alkylene-Z5 (XI)
wherein the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, may additionally be substituted by one or two Cx.2-alkyl groups or by an R60-CO or
Figure imgf000148_0001
group, whilst R6 in each case is defined as in claims 1 to 8, and Z5 denotes an exchangeable group, or
g) in order to prepare a compound of general formula I wherein at least one of the groups R6 to R8 denotes a hydrogen atom:
a compound of general formula
Figure imgf000148_0002
wherein
Ra to Rd, A, C and X are defined as in claims 1 to 8, B" and D" have the meanings given for B and D in claims 1 to 8, with the proviso that at least one of the groups B" or D" "contains an R60-CO, (R70-PO-OR8) or (R70-PO-R9) group wherein R9 is defined as in claims 1 to 8 and at least one of the groups R6 to R8 does not represent a hydrogen atom, is converted by hydrolysis, treating with acids, thermolysis or hydrogenolysis into a compound of general formula I wherein at least one of the groups R6 to R8 denotes a hydrogen atom,
and subsequently, if desired, a compound of general formula I thus obtained which contains a carboxy or hydroxyphosphoryl group is converted by esterification into a corresponding ester of general formula I and/or
a compound of general formula I thus obtained wherein B or D denotes an optionally substituted N- (2-hydroxyethyl) -glycine or N- (2-hydroxyethyl) -glycine ester group is converted by cyclisation into a corresponding 2-oxo-morpholino compound, and/or
if necessary any protecting group used during the reactions described above is cleaved again and/or
if desired a compound of general formula I thus obtained is resolved into its stereoisomers and/or
a compound of general formula I thus obtained is converted into the salts thereof, more particularly, for pharmaceutical use, into the physiologically acceptable salts thereof.
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